TW201739919A - 患者特異性新抗原決定基之高通量識別以作為用於癌症免疫療法之治療劑 - Google Patents
患者特異性新抗原決定基之高通量識別以作為用於癌症免疫療法之治療劑 Download PDFInfo
- Publication number
- TW201739919A TW201739919A TW106104528A TW106104528A TW201739919A TW 201739919 A TW201739919 A TW 201739919A TW 106104528 A TW106104528 A TW 106104528A TW 106104528 A TW106104528 A TW 106104528A TW 201739919 A TW201739919 A TW 201739919A
- Authority
- TW
- Taiwan
- Prior art keywords
- patient
- novel
- specific
- epitope
- cancer driver
- Prior art date
Links
- 230000001225 therapeutic effect Effects 0.000 title description 9
- 238000002619 cancer immunotherapy Methods 0.000 title description 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 251
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 170
- 201000011510 cancer Diseases 0.000 claims abstract description 156
- 238000000034 method Methods 0.000 claims abstract description 115
- 238000001914 filtration Methods 0.000 claims abstract description 40
- 210000004027 cell Anatomy 0.000 claims description 42
- 230000027455 binding Effects 0.000 claims description 32
- 150000007523 nucleic acids Chemical class 0.000 claims description 31
- 150000001413 amino acids Chemical class 0.000 claims description 30
- 102000039446 nucleic acids Human genes 0.000 claims description 30
- 108020004707 nucleic acids Proteins 0.000 claims description 30
- 102000004169 proteins and genes Human genes 0.000 claims description 30
- 241000700605 Viruses Species 0.000 claims description 23
- 238000009169 immunotherapy Methods 0.000 claims description 22
- 230000001024 immunotherapeutic effect Effects 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 16
- 108091092878 Microsatellite Proteins 0.000 claims description 15
- 102000054765 polymorphisms of proteins Human genes 0.000 claims description 15
- 239000000427 antigen Substances 0.000 claims description 14
- 108091007433 antigens Proteins 0.000 claims description 14
- 102000036639 antigens Human genes 0.000 claims description 14
- 238000012217 deletion Methods 0.000 claims description 14
- 230000037430 deletion Effects 0.000 claims description 14
- 238000003559 RNA-seq method Methods 0.000 claims description 13
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 11
- 238000003780 insertion Methods 0.000 claims description 11
- 230000037431 insertion Effects 0.000 claims description 11
- 239000002955 immunomodulating agent Substances 0.000 claims description 10
- 210000000822 natural killer cell Anatomy 0.000 claims description 10
- 229920000642 polymer Polymers 0.000 claims description 10
- 102000043129 MHC class I family Human genes 0.000 claims description 9
- 108091054437 MHC class I family Proteins 0.000 claims description 9
- 102000043131 MHC class II family Human genes 0.000 claims description 9
- 108091054438 MHC class II family Proteins 0.000 claims description 9
- 239000002773 nucleotide Substances 0.000 claims description 9
- 125000003729 nucleotide group Chemical group 0.000 claims description 9
- 238000012070 whole genome sequencing analysis Methods 0.000 claims description 9
- 101100268917 Oryctolagus cuniculus ACOX2 gene Proteins 0.000 claims description 8
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 8
- UCONUSSAWGCZMV-UHFFFAOYSA-N Tetrahydro-cannabinol-carbonsaeure Natural products O1C(C)(C)C2CCC(C)=CC2C2=C1C=C(CCCCC)C(C(O)=O)=C2O UCONUSSAWGCZMV-UHFFFAOYSA-N 0.000 claims description 8
- 210000004369 blood Anatomy 0.000 claims description 8
- 239000008280 blood Substances 0.000 claims description 8
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 8
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 7
- 238000004833 X-ray photoelectron spectroscopy Methods 0.000 claims description 7
- 230000000890 antigenic effect Effects 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 102000040430 polynucleotide Human genes 0.000 claims description 7
- 108091033319 polynucleotide Proteins 0.000 claims description 7
- 239000002157 polynucleotide Substances 0.000 claims description 7
- 238000007482 whole exome sequencing Methods 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000001802 infusion Methods 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 230000007257 malfunction Effects 0.000 claims 2
- 230000001900 immune effect Effects 0.000 claims 1
- 230000035772 mutation Effects 0.000 abstract description 20
- -1 at least two Chemical class 0.000 description 51
- 230000009977 dual effect Effects 0.000 description 41
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 25
- 102000015098 Tumor Suppressor Protein p53 Human genes 0.000 description 25
- 238000004458 analytical method Methods 0.000 description 24
- 102100034580 AT-rich interactive domain-containing protein 1A Human genes 0.000 description 19
- 101000924266 Homo sapiens AT-rich interactive domain-containing protein 1A Proteins 0.000 description 19
- 210000001519 tissue Anatomy 0.000 description 18
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 17
- 102000007530 Neurofibromin 1 Human genes 0.000 description 17
- 108010085793 Neurofibromin 1 Proteins 0.000 description 17
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 17
- 102100032543 Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN Human genes 0.000 description 17
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 description 17
- 102100030708 GTPase KRas Human genes 0.000 description 16
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 16
- 108010075704 HLA-A Antigens Proteins 0.000 description 16
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 16
- 102100028914 Catenin beta-1 Human genes 0.000 description 14
- 102100022102 Histone-lysine N-methyltransferase 2B Human genes 0.000 description 14
- 101000916173 Homo sapiens Catenin beta-1 Proteins 0.000 description 14
- 101001045848 Homo sapiens Histone-lysine N-methyltransferase 2B Proteins 0.000 description 14
- 101001008894 Homo sapiens Histone-lysine N-methyltransferase 2D Proteins 0.000 description 14
- 101001025967 Homo sapiens Lysine-specific demethylase 6A Proteins 0.000 description 14
- 101000707567 Homo sapiens Splicing factor 3B subunit 1 Proteins 0.000 description 14
- 102100037462 Lysine-specific demethylase 6A Human genes 0.000 description 14
- 102100032929 Son of sevenless homolog 1 Human genes 0.000 description 14
- 102100031711 Splicing factor 3B subunit 1 Human genes 0.000 description 14
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 14
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 14
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 14
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 13
- 102100023157 AT-rich interactive domain-containing protein 2 Human genes 0.000 description 13
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 description 13
- 102100039788 GTPase NRas Human genes 0.000 description 13
- 101000685261 Homo sapiens AT-rich interactive domain-containing protein 2 Proteins 0.000 description 13
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 13
- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 description 13
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 13
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 0.000 description 13
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 13
- 238000012163 sequencing technique Methods 0.000 description 13
- 101150020330 ATRX gene Proteins 0.000 description 12
- 108020004414 DNA Proteins 0.000 description 12
- 101710105178 F-box/WD repeat-containing protein 7 Proteins 0.000 description 12
- 102100028138 F-box/WD repeat-containing protein 7 Human genes 0.000 description 12
- 102100027755 Histone-lysine N-methyltransferase 2C Human genes 0.000 description 12
- 101001008892 Homo sapiens Histone-lysine N-methyltransferase 2C Proteins 0.000 description 12
- 101000742859 Homo sapiens Retinoblastoma-associated protein Proteins 0.000 description 12
- 101000666775 Homo sapiens T-box transcription factor TBX3 Proteins 0.000 description 12
- 101000649014 Homo sapiens Triple functional domain protein Proteins 0.000 description 12
- 102100038042 Retinoblastoma-associated protein Human genes 0.000 description 12
- 102100038409 T-box transcription factor TBX3 Human genes 0.000 description 12
- 102100023931 Transcriptional regulator ATRX Human genes 0.000 description 12
- 102100028101 Triple functional domain protein Human genes 0.000 description 12
- 108700042462 X-linked Nuclear Proteins 0.000 description 12
- 102100034571 AT-rich interactive domain-containing protein 1B Human genes 0.000 description 11
- 102100033391 ATP-dependent RNA helicase DDX3X Human genes 0.000 description 11
- 102100035673 Centrosomal protein of 290 kDa Human genes 0.000 description 11
- 101710198317 Centrosomal protein of 290 kDa Proteins 0.000 description 11
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 description 11
- 101000924255 Homo sapiens AT-rich interactive domain-containing protein 1B Proteins 0.000 description 11
- 101000870662 Homo sapiens ATP-dependent RNA helicase DDX3X Proteins 0.000 description 11
- 101000882390 Homo sapiens Histone acetyltransferase p300 Proteins 0.000 description 11
- 101001107586 Homo sapiens Nuclear pore complex protein Nup107 Proteins 0.000 description 11
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 11
- 101000703463 Homo sapiens Rho GTPase-activating protein 35 Proteins 0.000 description 11
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 11
- 102100023181 Neurogenic locus notch homolog protein 1 Human genes 0.000 description 11
- 108010029755 Notch1 Receptor Proteins 0.000 description 11
- 102100021976 Nuclear pore complex protein Nup107 Human genes 0.000 description 11
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 11
- 102100030676 Rho GTPase-activating protein 35 Human genes 0.000 description 11
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 11
- 102100033455 TGF-beta receptor type-2 Human genes 0.000 description 11
- 108010082684 Transforming Growth Factor-beta Type II Receptor Proteins 0.000 description 11
- 102000000872 ATM Human genes 0.000 description 10
- 102100036817 Ankyrin-3 Human genes 0.000 description 10
- 108010004586 Ataxia Telangiectasia Mutated Proteins Proteins 0.000 description 10
- 102100025422 Bone morphogenetic protein receptor type-2 Human genes 0.000 description 10
- 108091007854 Cdh1/Fizzy-related Proteins 0.000 description 10
- 102000038594 Cdh1/Fizzy-related Human genes 0.000 description 10
- 102100036569 Cell division cycle and apoptosis regulator protein 1 Human genes 0.000 description 10
- 102100039195 Cullin-1 Human genes 0.000 description 10
- 102100029952 Double-strand-break repair protein rad21 homolog Human genes 0.000 description 10
- 102100029987 Erbin Human genes 0.000 description 10
- 102100034174 Eukaryotic translation initiation factor 2-alpha kinase 3 Human genes 0.000 description 10
- 102100026353 F-box-like/WD repeat-containing protein TBL1XR1 Human genes 0.000 description 10
- 102100037362 Fibronectin Human genes 0.000 description 10
- 102100039121 Histone-lysine N-methyltransferase MECOM Human genes 0.000 description 10
- 101000928342 Homo sapiens Ankyrin-3 Proteins 0.000 description 10
- 101000934635 Homo sapiens Bone morphogenetic protein receptor type-2 Proteins 0.000 description 10
- 101000715197 Homo sapiens Cell division cycle and apoptosis regulator protein 1 Proteins 0.000 description 10
- 101000746063 Homo sapiens Cullin-1 Proteins 0.000 description 10
- 101000584942 Homo sapiens Double-strand-break repair protein rad21 homolog Proteins 0.000 description 10
- 101001095815 Homo sapiens E3 ubiquitin-protein ligase RING2 Proteins 0.000 description 10
- 101001010810 Homo sapiens Erbin Proteins 0.000 description 10
- 101000926508 Homo sapiens Eukaryotic translation initiation factor 2-alpha kinase 3 Proteins 0.000 description 10
- 101000835675 Homo sapiens F-box-like/WD repeat-containing protein TBL1XR1 Proteins 0.000 description 10
- 101001027128 Homo sapiens Fibronectin Proteins 0.000 description 10
- 101100076418 Homo sapiens MECOM gene Proteins 0.000 description 10
- 101000614988 Homo sapiens Mediator of RNA polymerase II transcription subunit 12 Proteins 0.000 description 10
- 101001057193 Homo sapiens Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 Proteins 0.000 description 10
- 101000934489 Homo sapiens Nucleosome-remodeling factor subunit BPTF Proteins 0.000 description 10
- 101001120056 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit alpha Proteins 0.000 description 10
- 101000893674 Homo sapiens Ras GTPase-activating protein-binding protein 2 Proteins 0.000 description 10
- 101000596771 Homo sapiens Transcription factor 7-like 2 Proteins 0.000 description 10
- 101000740048 Homo sapiens Ubiquitin carboxyl-terminal hydrolase BAP1 Proteins 0.000 description 10
- 101000740049 Latilactobacillus curvatus Bioactive peptide 1 Proteins 0.000 description 10
- 108700024831 MDS1 and EVI1 Complex Locus Proteins 0.000 description 10
- 102100021070 Mediator of RNA polymerase II transcription subunit 12 Human genes 0.000 description 10
- 102100027240 Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 Human genes 0.000 description 10
- 102100025725 Mothers against decapentaplegic homolog 4 Human genes 0.000 description 10
- 101710143112 Mothers against decapentaplegic homolog 4 Proteins 0.000 description 10
- 108010071382 NF-E2-Related Factor 2 Proteins 0.000 description 10
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 description 10
- 102100025372 Nuclear pore complex protein Nup98-Nup96 Human genes 0.000 description 10
- 102100025062 Nucleosome-remodeling factor subunit BPTF Human genes 0.000 description 10
- 102100026169 Phosphatidylinositol 3-kinase regulatory subunit alpha Human genes 0.000 description 10
- 102100040857 Ras GTPase-activating protein-binding protein 2 Human genes 0.000 description 10
- 102100035101 Transcription factor 7-like 2 Human genes 0.000 description 10
- 230000014509 gene expression Effects 0.000 description 10
- 108010054452 nuclear pore complex protein 98 Proteins 0.000 description 10
- 102100040084 A-kinase anchor protein 9 Human genes 0.000 description 9
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 9
- 102100021247 BCL-6 corepressor Human genes 0.000 description 9
- 102100031033 CCR4-NOT transcription complex subunit 3 Human genes 0.000 description 9
- 102100021975 CREB-binding protein Human genes 0.000 description 9
- 102100026548 Caspase-8 Human genes 0.000 description 9
- 102100040484 Claspin Human genes 0.000 description 9
- 102100035595 Cohesin subunit SA-2 Human genes 0.000 description 9
- 102100038111 Cyclin-dependent kinase 12 Human genes 0.000 description 9
- 102100022462 Eukaryotic initiation factor 4A-II Human genes 0.000 description 9
- 102100039735 Eukaryotic translation initiation factor 4 gamma 1 Human genes 0.000 description 9
- 102100024359 Exosome complex exonuclease RRP44 Human genes 0.000 description 9
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 9
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 9
- 102100022103 Histone-lysine N-methyltransferase 2A Human genes 0.000 description 9
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 description 9
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 9
- 102100023696 Histone-lysine N-methyltransferase SETDB1 Human genes 0.000 description 9
- 101000890598 Homo sapiens A-kinase anchor protein 9 Proteins 0.000 description 9
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 description 9
- 101100165236 Homo sapiens BCOR gene Proteins 0.000 description 9
- 101000919663 Homo sapiens CCR4-NOT transcription complex subunit 3 Proteins 0.000 description 9
- 101000896987 Homo sapiens CREB-binding protein Proteins 0.000 description 9
- 101000983528 Homo sapiens Caspase-8 Proteins 0.000 description 9
- 101000750011 Homo sapiens Claspin Proteins 0.000 description 9
- 101000642968 Homo sapiens Cohesin subunit SA-2 Proteins 0.000 description 9
- 101000884345 Homo sapiens Cyclin-dependent kinase 12 Proteins 0.000 description 9
- 101001044475 Homo sapiens Eukaryotic initiation factor 4A-II Proteins 0.000 description 9
- 101001034825 Homo sapiens Eukaryotic translation initiation factor 4 gamma 1 Proteins 0.000 description 9
- 101000627103 Homo sapiens Exosome complex exonuclease RRP44 Proteins 0.000 description 9
- 101001045846 Homo sapiens Histone-lysine N-methyltransferase 2A Proteins 0.000 description 9
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 description 9
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 9
- 101000684609 Homo sapiens Histone-lysine N-methyltransferase SETDB1 Proteins 0.000 description 9
- 101001056724 Homo sapiens Intersectin-1 Proteins 0.000 description 9
- 101000692980 Homo sapiens PHD finger protein 6 Proteins 0.000 description 9
- 101000601770 Homo sapiens Protein polybromo-1 Proteins 0.000 description 9
- 101001072227 Homo sapiens Protocadherin-18 Proteins 0.000 description 9
- 101000633429 Homo sapiens Structural maintenance of chromosomes protein 1A Proteins 0.000 description 9
- 101000596093 Homo sapiens Transcription initiation factor TFIID subunit 1 Proteins 0.000 description 9
- 101001087416 Homo sapiens Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 9
- 101000788845 Homo sapiens Zinc finger CCCH domain-containing protein 11A Proteins 0.000 description 9
- 101000976415 Homo sapiens Zinc finger protein 814 Proteins 0.000 description 9
- 102100025494 Intersectin-1 Human genes 0.000 description 9
- 102000004901 Iron regulatory protein 1 Human genes 0.000 description 9
- 108090001025 Iron regulatory protein 1 Proteins 0.000 description 9
- 102100026365 PHD finger protein 6 Human genes 0.000 description 9
- 102100037516 Protein polybromo-1 Human genes 0.000 description 9
- 102100036397 Protocadherin-18 Human genes 0.000 description 9
- 102100029538 Structural maintenance of chromosomes protein 1A Human genes 0.000 description 9
- 102100035222 Transcription initiation factor TFIID subunit 1 Human genes 0.000 description 9
- 102000000504 Tumor Suppressor p53-Binding Protein 1 Human genes 0.000 description 9
- 108010041385 Tumor Suppressor p53-Binding Protein 1 Proteins 0.000 description 9
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 description 9
- 102100025402 Zinc finger CCCH domain-containing protein 11A Human genes 0.000 description 9
- 102100023595 Zinc finger protein 814 Human genes 0.000 description 9
- QYAPHLRPFNSDNH-MRFRVZCGSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O QYAPHLRPFNSDNH-MRFRVZCGSA-N 0.000 description 8
- 102100024381 AF4/FMR2 family member 4 Human genes 0.000 description 8
- 102100025684 APC membrane recruitment protein 1 Human genes 0.000 description 8
- 102100030374 Actin, cytoplasmic 2 Human genes 0.000 description 8
- 102100034134 Activin receptor type-1B Human genes 0.000 description 8
- 102000036365 BRCA1 Human genes 0.000 description 8
- 108700020463 BRCA1 Proteins 0.000 description 8
- 101150072950 BRCA1 gene Proteins 0.000 description 8
- 102100032423 Bcl-2-associated transcription factor 1 Human genes 0.000 description 8
- 102100028573 Brefeldin A-inhibited guanine nucleotide-exchange protein 2 Human genes 0.000 description 8
- 108010014064 CCCTC-Binding Factor Proteins 0.000 description 8
- 102100031024 CCR4-NOT transcription complex subunit 1 Human genes 0.000 description 8
- 102100029395 CLIP-associating protein 2 Human genes 0.000 description 8
- 102100038214 Chromodomain-helicase-DNA-binding protein 4 Human genes 0.000 description 8
- 101710082464 Cis-aconitate decarboxylase Proteins 0.000 description 8
- 102100026127 Clathrin heavy chain 1 Human genes 0.000 description 8
- 108010016777 Cyclin-Dependent Kinase Inhibitor p27 Proteins 0.000 description 8
- 102000000577 Cyclin-Dependent Kinase Inhibitor p27 Human genes 0.000 description 8
- 102100024812 DNA (cytosine-5)-methyltransferase 3A Human genes 0.000 description 8
- 108010024491 DNA Methyltransferase 3A Proteins 0.000 description 8
- 101710147299 DNA fragmentation factor subunit beta Proteins 0.000 description 8
- 102100028843 DNA mismatch repair protein Mlh1 Human genes 0.000 description 8
- 102100034581 Dihydroorotase Human genes 0.000 description 8
- 102100036118 Far upstream element-binding protein 1 Human genes 0.000 description 8
- 102100032510 Heat shock protein HSP 90-beta Human genes 0.000 description 8
- 102100027706 Heterogeneous nuclear ribonucleoprotein D-like Human genes 0.000 description 8
- 101000833170 Homo sapiens AF4/FMR2 family member 4 Proteins 0.000 description 8
- 101000719162 Homo sapiens APC membrane recruitment protein 1 Proteins 0.000 description 8
- 101000773237 Homo sapiens Actin, cytoplasmic 2 Proteins 0.000 description 8
- 101000799189 Homo sapiens Activin receptor type-1B Proteins 0.000 description 8
- 101000798490 Homo sapiens Bcl-2-associated transcription factor 1 Proteins 0.000 description 8
- 101000695920 Homo sapiens Brefeldin A-inhibited guanine nucleotide-exchange protein 2 Proteins 0.000 description 8
- 101000919672 Homo sapiens CCR4-NOT transcription complex subunit 1 Proteins 0.000 description 8
- 101000989987 Homo sapiens CLIP-associating protein 2 Proteins 0.000 description 8
- 101000883749 Homo sapiens Chromodomain-helicase-DNA-binding protein 4 Proteins 0.000 description 8
- 101000912851 Homo sapiens Clathrin heavy chain 1 Proteins 0.000 description 8
- 101000930770 Homo sapiens Far upstream element-binding protein 1 Proteins 0.000 description 8
- 101001016856 Homo sapiens Heat shock protein HSP 90-beta Proteins 0.000 description 8
- 101001081145 Homo sapiens Heterogeneous nuclear ribonucleoprotein D-like Proteins 0.000 description 8
- 101000972918 Homo sapiens MAX gene-associated protein Proteins 0.000 description 8
- 101001134216 Homo sapiens Macrophage scavenger receptor types I and II Proteins 0.000 description 8
- 101001052076 Homo sapiens Maltase-glucoamylase Proteins 0.000 description 8
- 101001018147 Homo sapiens Mitogen-activated protein kinase kinase kinase 4 Proteins 0.000 description 8
- 101000591286 Homo sapiens Myocardin-related transcription factor A Proteins 0.000 description 8
- 101001024714 Homo sapiens Nck-associated protein 1 Proteins 0.000 description 8
- 101000974340 Homo sapiens Nuclear receptor corepressor 1 Proteins 0.000 description 8
- 101001109698 Homo sapiens Nuclear receptor subfamily 4 group A member 2 Proteins 0.000 description 8
- 101000595741 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Proteins 0.000 description 8
- 101001105683 Homo sapiens Pre-mRNA-processing-splicing factor 8 Proteins 0.000 description 8
- 101000952113 Homo sapiens Probable ATP-dependent RNA helicase DDX5 Proteins 0.000 description 8
- 101001130509 Homo sapiens Ras GTPase-activating protein 1 Proteins 0.000 description 8
- 101000727472 Homo sapiens Reticulon-4 Proteins 0.000 description 8
- 101001091984 Homo sapiens Rho GTPase-activating protein 26 Proteins 0.000 description 8
- 101000838578 Homo sapiens Serine/threonine-protein kinase TAO2 Proteins 0.000 description 8
- 101000783404 Homo sapiens Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform Proteins 0.000 description 8
- 101000828537 Homo sapiens Synaptic functional regulator FMR1 Proteins 0.000 description 8
- 101000653663 Homo sapiens T-complex protein 1 subunit epsilon Proteins 0.000 description 8
- 101000802356 Homo sapiens Tight junction protein ZO-1 Proteins 0.000 description 8
- 101000711846 Homo sapiens Transcription factor SOX-9 Proteins 0.000 description 8
- 108010007666 IMP cyclohydrolase Proteins 0.000 description 8
- 102100020796 Inosine 5'-monophosphate cyclohydrolase Human genes 0.000 description 8
- 102000004902 Iron regulatory protein 2 Human genes 0.000 description 8
- 108090001028 Iron regulatory protein 2 Proteins 0.000 description 8
- 108010075654 MAP Kinase Kinase Kinase 1 Proteins 0.000 description 8
- 102100022621 MAX gene-associated protein Human genes 0.000 description 8
- 102100034184 Macrophage scavenger receptor types I and II Human genes 0.000 description 8
- 102100033115 Mitogen-activated protein kinase kinase kinase 1 Human genes 0.000 description 8
- 102100033060 Mitogen-activated protein kinase kinase kinase 4 Human genes 0.000 description 8
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 description 8
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 description 8
- 101150097381 Mtor gene Proteins 0.000 description 8
- 108010026664 MutL Protein Homolog 1 Proteins 0.000 description 8
- 102100034099 Myocardin-related transcription factor A Human genes 0.000 description 8
- 102100036954 Nck-associated protein 1 Human genes 0.000 description 8
- 102100022935 Nuclear receptor corepressor 1 Human genes 0.000 description 8
- 102100022676 Nuclear receptor subfamily 4 group A member 2 Human genes 0.000 description 8
- 102100036061 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Human genes 0.000 description 8
- 102100021231 Pre-mRNA-processing-splicing factor 8 Human genes 0.000 description 8
- 102100037434 Probable ATP-dependent RNA helicase DDX5 Human genes 0.000 description 8
- 101710145525 Probable cinnamyl alcohol dehydrogenase Proteins 0.000 description 8
- 102100031426 Ras GTPase-activating protein 1 Human genes 0.000 description 8
- 102100029831 Reticulon-4 Human genes 0.000 description 8
- 102100035744 Rho GTPase-activating protein 26 Human genes 0.000 description 8
- 102100028949 Serine/threonine-protein kinase TAO2 Human genes 0.000 description 8
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 8
- 102100036122 Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform Human genes 0.000 description 8
- 102100023532 Synaptic functional regulator FMR1 Human genes 0.000 description 8
- 102100029886 T-complex protein 1 subunit epsilon Human genes 0.000 description 8
- 102100034686 Tight junction protein ZO-1 Human genes 0.000 description 8
- 108090001097 Transcription Factor DP1 Proteins 0.000 description 8
- 102000004853 Transcription Factor DP1 Human genes 0.000 description 8
- 102100034204 Transcription factor SOX-9 Human genes 0.000 description 8
- 102100027671 Transcriptional repressor CTCF Human genes 0.000 description 8
- 108700020467 WT1 Proteins 0.000 description 8
- 101150084041 WT1 gene Proteins 0.000 description 8
- 102100022748 Wilms tumor protein Human genes 0.000 description 8
- 102100026750 60S ribosomal protein L5 Human genes 0.000 description 7
- 108091007504 ADAM10 Proteins 0.000 description 7
- 102100023388 ATP-dependent RNA helicase DHX15 Human genes 0.000 description 7
- 102100036791 Adhesion G protein-coupled receptor L2 Human genes 0.000 description 7
- 101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 description 7
- 102100031239 Chromodomain-helicase-DNA-binding protein 1-like Human genes 0.000 description 7
- 102100031266 Chromodomain-helicase-DNA-binding protein 3 Human genes 0.000 description 7
- 102100038164 Chromodomain-helicase-DNA-binding protein 9 Human genes 0.000 description 7
- 102100035590 Cohesin subunit SA-1 Human genes 0.000 description 7
- 108010043471 Core Binding Factor Alpha 2 Subunit Proteins 0.000 description 7
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 description 7
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 7
- 102100039303 DNA-directed RNA polymerase II subunit RPB2 Human genes 0.000 description 7
- 102100039673 Disintegrin and metalloproteinase domain-containing protein 10 Human genes 0.000 description 7
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 7
- 102100023387 Endoribonuclease Dicer Human genes 0.000 description 7
- 102100041032 Golgin subfamily A member 5 Human genes 0.000 description 7
- 102100032610 Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas Human genes 0.000 description 7
- 102100027421 Heat shock cognate 71 kDa protein Human genes 0.000 description 7
- 102100029239 Histone-lysine N-methyltransferase, H3 lysine-36 specific Human genes 0.000 description 7
- 101000691083 Homo sapiens 60S ribosomal protein L5 Proteins 0.000 description 7
- 101000907886 Homo sapiens ATP-dependent RNA helicase DHX15 Proteins 0.000 description 7
- 101000928189 Homo sapiens Adhesion G protein-coupled receptor L2 Proteins 0.000 description 7
- 101000777053 Homo sapiens Chromodomain-helicase-DNA-binding protein 1-like Proteins 0.000 description 7
- 101000777071 Homo sapiens Chromodomain-helicase-DNA-binding protein 3 Proteins 0.000 description 7
- 101000883548 Homo sapiens Chromodomain-helicase-DNA-binding protein 9 Proteins 0.000 description 7
- 101000642971 Homo sapiens Cohesin subunit SA-1 Proteins 0.000 description 7
- 101000669831 Homo sapiens DNA-directed RNA polymerase II subunit RPB2 Proteins 0.000 description 7
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 7
- 101000907904 Homo sapiens Endoribonuclease Dicer Proteins 0.000 description 7
- 101001039330 Homo sapiens Golgin subfamily A member 5 Proteins 0.000 description 7
- 101001014590 Homo sapiens Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas Proteins 0.000 description 7
- 101001014594 Homo sapiens Guanine nucleotide-binding protein G(s) subunit alpha isoforms short Proteins 0.000 description 7
- 101001080568 Homo sapiens Heat shock cognate 71 kDa protein Proteins 0.000 description 7
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 description 7
- 101000634050 Homo sapiens Histone-lysine N-methyltransferase, H3 lysine-36 specific Proteins 0.000 description 7
- 101001077600 Homo sapiens Insulin receptor substrate 2 Proteins 0.000 description 7
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 7
- 101000575066 Homo sapiens Mediator of RNA polymerase II transcription subunit 17 Proteins 0.000 description 7
- 101000582846 Homo sapiens Mediator of RNA polymerase II transcription subunit 22 Proteins 0.000 description 7
- 101001019109 Homo sapiens Mediator of RNA polymerase II transcription subunit 24 Proteins 0.000 description 7
- 101001000109 Homo sapiens Myosin-10 Proteins 0.000 description 7
- 101000775053 Homo sapiens Neuroblast differentiation-associated protein AHNAK Proteins 0.000 description 7
- 101001014610 Homo sapiens Neuroendocrine secretory protein 55 Proteins 0.000 description 7
- 101000651906 Homo sapiens Paired amphipathic helix protein Sin3a Proteins 0.000 description 7
- 101000601724 Homo sapiens Paired box protein Pax-5 Proteins 0.000 description 7
- 101000730454 Homo sapiens Phosphatidylinositol 4-phosphate 5-kinase type-1 alpha Proteins 0.000 description 7
- 101000584499 Homo sapiens Polycomb protein SUZ12 Proteins 0.000 description 7
- 101000797903 Homo sapiens Protein ALEX Proteins 0.000 description 7
- 101000620365 Homo sapiens Protein TMEPAI Proteins 0.000 description 7
- 101000690503 Homo sapiens Protein argonaute-3 Proteins 0.000 description 7
- 101000883014 Homo sapiens Protein capicua homolog Proteins 0.000 description 7
- 101000824318 Homo sapiens Protocadherin Fat 1 Proteins 0.000 description 7
- 101000927086 Homo sapiens RNA helicase aquarius Proteins 0.000 description 7
- 101000927799 Homo sapiens Rho guanine nucleotide exchange factor 6 Proteins 0.000 description 7
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 description 7
- 101000795185 Homo sapiens Thyroid hormone receptor-associated protein 3 Proteins 0.000 description 7
- 101001041525 Homo sapiens Transcription factor 12 Proteins 0.000 description 7
- 101000802101 Homo sapiens mRNA decay activator protein ZFP36L2 Proteins 0.000 description 7
- 102100025092 Insulin receptor substrate 2 Human genes 0.000 description 7
- 108090000484 Kelch-Like ECH-Associated Protein 1 Proteins 0.000 description 7
- 102000004034 Kelch-Like ECH-Associated Protein 1 Human genes 0.000 description 7
- 102100025530 Mediator of RNA polymerase II transcription subunit 17 Human genes 0.000 description 7
- 102100034821 Mediator of RNA polymerase II transcription subunit 24 Human genes 0.000 description 7
- 102100036640 Myosin-10 Human genes 0.000 description 7
- 102100031837 Neuroblast differentiation-associated protein AHNAK Human genes 0.000 description 7
- 102100027334 Paired amphipathic helix protein Sin3a Human genes 0.000 description 7
- 102100037504 Paired box protein Pax-5 Human genes 0.000 description 7
- 102100032615 Phosphatidylinositol 4-phosphate 5-kinase type-1 alpha Human genes 0.000 description 7
- 102100030702 Polycomb protein SUZ12 Human genes 0.000 description 7
- 102100026791 Protein argonaute-3 Human genes 0.000 description 7
- 102100038777 Protein capicua homolog Human genes 0.000 description 7
- 102100022095 Protocadherin Fat 1 Human genes 0.000 description 7
- 102100033483 RNA helicase aquarius Human genes 0.000 description 7
- 102100033202 Rho guanine nucleotide exchange factor 6 Human genes 0.000 description 7
- 102100025373 Runt-related transcription factor 1 Human genes 0.000 description 7
- 108700022176 SOS1 Proteins 0.000 description 7
- 101100197320 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPL35A gene Proteins 0.000 description 7
- 101150100839 Sos1 gene Proteins 0.000 description 7
- 102100029689 Thyroid hormone receptor-associated protein 3 Human genes 0.000 description 7
- 102100021123 Transcription factor 12 Human genes 0.000 description 7
- 238000004422 calculation algorithm Methods 0.000 description 7
- 102100034703 mRNA decay activator protein ZFP36L2 Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 102100022117 Abnormal spindle-like microcephaly-associated protein Human genes 0.000 description 6
- 102100035631 Bloom syndrome protein Human genes 0.000 description 6
- 108091009167 Bloom syndrome protein Proteins 0.000 description 6
- 102100021574 Bromodomain adjacent to zinc finger domain protein 2B Human genes 0.000 description 6
- 102100032981 CCR4-NOT transcription complex subunit 4 Human genes 0.000 description 6
- 102100027652 COP9 signalosome complex subunit 2 Human genes 0.000 description 6
- 102100023067 Casein kinase I isoform gamma-3 Human genes 0.000 description 6
- 102100031634 Cold shock domain-containing protein E1 Human genes 0.000 description 6
- 102100039193 Cullin-2 Human genes 0.000 description 6
- 102100028908 Cullin-3 Human genes 0.000 description 6
- 101100226017 Dictyostelium discoideum repD gene Proteins 0.000 description 6
- 102100024099 Disks large homolog 1 Human genes 0.000 description 6
- 102100035493 E3 ubiquitin-protein ligase NEDD4-like Human genes 0.000 description 6
- 101150105460 ERCC2 gene Proteins 0.000 description 6
- 101000914063 Eucalyptus globulus Leafy/floricaula homolog FL1 Proteins 0.000 description 6
- 102100028122 Forkhead box protein P1 Human genes 0.000 description 6
- 102100036334 Fragile X mental retardation syndrome-related protein 1 Human genes 0.000 description 6
- 102100029974 GTPase HRas Human genes 0.000 description 6
- 102100035184 General transcription and DNA repair factor IIH helicase subunit XPD Human genes 0.000 description 6
- 102100028976 HLA class I histocompatibility antigen, B alpha chain Human genes 0.000 description 6
- 108010058607 HLA-B Antigens Proteins 0.000 description 6
- 102100028896 Heterogeneous nuclear ribonucleoprotein Q Human genes 0.000 description 6
- 102100025210 Histone-arginine methyltransferase CARM1 Human genes 0.000 description 6
- 102100026265 Histone-lysine N-methyltransferase ASH1L Human genes 0.000 description 6
- 101000900939 Homo sapiens Abnormal spindle-like microcephaly-associated protein Proteins 0.000 description 6
- 101000971143 Homo sapiens Bromodomain adjacent to zinc finger domain protein 2B Proteins 0.000 description 6
- 101000942594 Homo sapiens CCR4-NOT transcription complex subunit 4 Proteins 0.000 description 6
- 101000726004 Homo sapiens COP9 signalosome complex subunit 2 Proteins 0.000 description 6
- 101001049879 Homo sapiens Casein kinase I isoform gamma-3 Proteins 0.000 description 6
- 101000940535 Homo sapiens Cold shock domain-containing protein E1 Proteins 0.000 description 6
- 101000746072 Homo sapiens Cullin-2 Proteins 0.000 description 6
- 101000916238 Homo sapiens Cullin-3 Proteins 0.000 description 6
- 101001053984 Homo sapiens Disks large homolog 1 Proteins 0.000 description 6
- 101000951365 Homo sapiens Disks large-associated protein 5 Proteins 0.000 description 6
- 101001023703 Homo sapiens E3 ubiquitin-protein ligase NEDD4-like Proteins 0.000 description 6
- 101000877395 Homo sapiens ETS-related transcription factor Elf-1 Proteins 0.000 description 6
- 101001059893 Homo sapiens Forkhead box protein P1 Proteins 0.000 description 6
- 101000930945 Homo sapiens Fragile X mental retardation syndrome-related protein 1 Proteins 0.000 description 6
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 6
- 101000839069 Homo sapiens Heterogeneous nuclear ribonucleoprotein Q Proteins 0.000 description 6
- 101000785963 Homo sapiens Histone-lysine N-methyltransferase ASH1L Proteins 0.000 description 6
- 101001050038 Homo sapiens Kalirin Proteins 0.000 description 6
- 101000780202 Homo sapiens Long-chain-fatty-acid-CoA ligase 6 Proteins 0.000 description 6
- 101001039199 Homo sapiens Low-density lipoprotein receptor-related protein 6 Proteins 0.000 description 6
- 101001088887 Homo sapiens Lysine-specific demethylase 5C Proteins 0.000 description 6
- 101000578920 Homo sapiens Microtubule-actin cross-linking factor 1, isoforms 1/2/3/5 Proteins 0.000 description 6
- 101001059989 Homo sapiens Mitogen-activated protein kinase kinase kinase kinase 3 Proteins 0.000 description 6
- 101001112224 Homo sapiens Neutrophil cytosol factor 2 Proteins 0.000 description 6
- 101001098116 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit gamma Proteins 0.000 description 6
- 101001098833 Homo sapiens Proprotein convertase subtilisin/kexin type 6 Proteins 0.000 description 6
- 101000979748 Homo sapiens Protein NDRG1 Proteins 0.000 description 6
- 101000822339 Homo sapiens Protein transport protein Sec24D Proteins 0.000 description 6
- 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 6
- 101000695838 Homo sapiens Receptor-type tyrosine-protein phosphatase U Proteins 0.000 description 6
- 101000868154 Homo sapiens Son of sevenless homolog 2 Proteins 0.000 description 6
- 101000704203 Homo sapiens Spectrin alpha chain, non-erythrocytic 1 Proteins 0.000 description 6
- 101000785523 Homo sapiens Tight junction protein ZO-2 Proteins 0.000 description 6
- 101000881764 Homo sapiens Transcription elongation factor 1 homolog Proteins 0.000 description 6
- 101000648491 Homo sapiens Transportin-1 Proteins 0.000 description 6
- 101000650141 Homo sapiens WAS/WASL-interacting protein family member 1 Proteins 0.000 description 6
- 101000788669 Homo sapiens Zinc finger MYM-type protein 2 Proteins 0.000 description 6
- 102100023093 Kalirin Human genes 0.000 description 6
- 102100034337 Long-chain-fatty-acid-CoA ligase 6 Human genes 0.000 description 6
- 102100040704 Low-density lipoprotein receptor-related protein 6 Human genes 0.000 description 6
- 102100033249 Lysine-specific demethylase 5C Human genes 0.000 description 6
- 102100028322 Microtubule-actin cross-linking factor 1, isoforms 1/2/3/5 Human genes 0.000 description 6
- 102100028193 Mitogen-activated protein kinase kinase kinase kinase 3 Human genes 0.000 description 6
- 102100023618 Neutrophil cytosol factor 2 Human genes 0.000 description 6
- 102100037553 Phosphatidylinositol 3-kinase regulatory subunit gamma Human genes 0.000 description 6
- 102100038946 Proprotein convertase subtilisin/kexin type 6 Human genes 0.000 description 6
- 102100024980 Protein NDRG1 Human genes 0.000 description 6
- 102100022542 Protein transport protein Sec24D Human genes 0.000 description 6
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 6
- 101150111584 RHOA gene Proteins 0.000 description 6
- 102100028516 Receptor-type tyrosine-protein phosphatase U Human genes 0.000 description 6
- 102100037375 SLIT-ROBO Rho GTPase-activating protein 3 Human genes 0.000 description 6
- 101150083405 SRGAP3 gene Proteins 0.000 description 6
- 102100032930 Son of sevenless homolog 2 Human genes 0.000 description 6
- 102100031874 Spectrin alpha chain, non-erythrocytic 1 Human genes 0.000 description 6
- 102100026637 Tight junction protein ZO-2 Human genes 0.000 description 6
- 102100037116 Transcription elongation factor 1 homolog Human genes 0.000 description 6
- 102100022387 Transforming protein RhoA Human genes 0.000 description 6
- 102100028748 Transportin-1 Human genes 0.000 description 6
- 102100027538 WAS/WASL-interacting protein family member 1 Human genes 0.000 description 6
- 108700031763 Xeroderma Pigmentosum Group D Proteins 0.000 description 6
- 102100025085 Zinc finger MYM-type protein 2 Human genes 0.000 description 6
- ZPCCSZFPOXBNDL-ZSTSFXQOSA-N [(4r,5s,6s,7r,9r,10r,11e,13e,16r)-6-[(2s,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2r,5s,6r)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-5-methoxy-9,16-dimethyl-2-oxo-7-(2-oxoe Chemical compound O([C@H]1/C=C/C=C/C[C@@H](C)OC(=O)C[C@H]([C@@H]([C@H]([C@@H](CC=O)C[C@H]1C)O[C@H]1[C@@H]([C@H]([C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1)N(C)C)O)OC)OC(C)=O)[C@H]1CC[C@H](N(C)C)[C@@H](C)O1 ZPCCSZFPOXBNDL-ZSTSFXQOSA-N 0.000 description 6
- 108010030886 coactivator-associated arginine methyltransferase 1 Proteins 0.000 description 6
- 230000028993 immune response Effects 0.000 description 6
- 238000000575 proteomic method Methods 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 102100037685 60S ribosomal protein L22 Human genes 0.000 description 5
- 102100033281 ADP-ribosylation factor GTPase-activating protein 3 Human genes 0.000 description 5
- 102100021886 Activin receptor type-2A Human genes 0.000 description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 5
- 108010080691 Alcohol O-acetyltransferase Proteins 0.000 description 5
- 102100037211 Aryl hydrocarbon receptor nuclear translocator-like protein 1 Human genes 0.000 description 5
- 102100029892 Bromodomain and WD repeat-containing protein 1 Human genes 0.000 description 5
- 102100028226 COUP transcription factor 2 Human genes 0.000 description 5
- 102100035904 Caspase-1 Human genes 0.000 description 5
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 description 5
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 5
- 102100035079 ETS-related transcription factor Elf-3 Human genes 0.000 description 5
- 102100030801 Elongation factor 1-alpha 1 Human genes 0.000 description 5
- 102100039408 Eukaryotic translation initiation factor 1A, X-chromosomal Human genes 0.000 description 5
- 102100033295 Glial cell line-derived neurotrophic factor Human genes 0.000 description 5
- 101001097555 Homo sapiens 60S ribosomal protein L22 Proteins 0.000 description 5
- 101000927505 Homo sapiens ADP-ribosylation factor GTPase-activating protein 3 Proteins 0.000 description 5
- 101000756632 Homo sapiens Actin, cytoplasmic 1 Proteins 0.000 description 5
- 101000970954 Homo sapiens Activin receptor type-2A Proteins 0.000 description 5
- 101000740484 Homo sapiens Aryl hydrocarbon receptor nuclear translocator-like protein 1 Proteins 0.000 description 5
- 101000794040 Homo sapiens Bromodomain and WD repeat-containing protein 1 Proteins 0.000 description 5
- 101000860860 Homo sapiens COUP transcription factor 2 Proteins 0.000 description 5
- 101000715398 Homo sapiens Caspase-1 Proteins 0.000 description 5
- 101000877379 Homo sapiens ETS-related transcription factor Elf-3 Proteins 0.000 description 5
- 101000920078 Homo sapiens Elongation factor 1-alpha 1 Proteins 0.000 description 5
- 101001036349 Homo sapiens Eukaryotic translation initiation factor 1A, X-chromosomal Proteins 0.000 description 5
- 101000677562 Homo sapiens Isobutyryl-CoA dehydrogenase, mitochondrial Proteins 0.000 description 5
- 101001139134 Homo sapiens Krueppel-like factor 4 Proteins 0.000 description 5
- 101001139126 Homo sapiens Krueppel-like factor 6 Proteins 0.000 description 5
- 101000582631 Homo sapiens Menin Proteins 0.000 description 5
- 101000954986 Homo sapiens Merlin Proteins 0.000 description 5
- 101001013159 Homo sapiens Myeloid leukemia factor 2 Proteins 0.000 description 5
- 101000995164 Homo sapiens Netrin-4 Proteins 0.000 description 5
- 101001069727 Homo sapiens Paired mesoderm homeobox protein 1 Proteins 0.000 description 5
- 101000945735 Homo sapiens Parafibromin Proteins 0.000 description 5
- 101000596046 Homo sapiens Plastin-2 Proteins 0.000 description 5
- 101000605122 Homo sapiens Prostaglandin G/H synthase 1 Proteins 0.000 description 5
- 101000743272 Homo sapiens RNA-binding protein 5 Proteins 0.000 description 5
- 101000880431 Homo sapiens Serine/threonine-protein kinase 4 Proteins 0.000 description 5
- 101000642268 Homo sapiens Speckle-type POZ protein Proteins 0.000 description 5
- 101000648153 Homo sapiens Stress-induced-phosphoprotein 1 Proteins 0.000 description 5
- 101000762938 Homo sapiens TOX high mobility group box family member 4 Proteins 0.000 description 5
- 101000819111 Homo sapiens Trans-acting T-cell-specific transcription factor GATA-3 Proteins 0.000 description 5
- 101000976959 Homo sapiens Transcription factor 4 Proteins 0.000 description 5
- 101000636213 Homo sapiens Transcriptional activator Myb Proteins 0.000 description 5
- 101000740482 Homo sapiens Zinc finger protein basonuclin-2 Proteins 0.000 description 5
- 102100021646 Isobutyryl-CoA dehydrogenase, mitochondrial Human genes 0.000 description 5
- 102100020677 Krueppel-like factor 4 Human genes 0.000 description 5
- 102100020679 Krueppel-like factor 6 Human genes 0.000 description 5
- 108010068342 MAP Kinase Kinase 1 Proteins 0.000 description 5
- 102100030550 Menin Human genes 0.000 description 5
- 102100037106 Merlin Human genes 0.000 description 5
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 5
- 102100029687 Myeloid leukemia factor 2 Human genes 0.000 description 5
- 108010018525 NFATC Transcription Factors Proteins 0.000 description 5
- 102000002673 NFATC Transcription Factors Human genes 0.000 description 5
- 102100033786 Paired mesoderm homeobox protein 1 Human genes 0.000 description 5
- 102100034743 Parafibromin Human genes 0.000 description 5
- 102100035182 Plastin-2 Human genes 0.000 description 5
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 5
- 102100038152 RNA-binding protein 5 Human genes 0.000 description 5
- 102100037629 Serine/threonine-protein kinase 4 Human genes 0.000 description 5
- 102100028948 Serine/threonine-protein kinase TAO1 Human genes 0.000 description 5
- 101710106079 Serine/threonine-protein kinase TAO1 Proteins 0.000 description 5
- 102100036422 Speckle-type POZ protein Human genes 0.000 description 5
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 5
- 102100025292 Stress-induced-phosphoprotein 1 Human genes 0.000 description 5
- 102100021386 Trans-acting T-cell-specific transcription factor GATA-3 Human genes 0.000 description 5
- 102100030780 Transcriptional activator Myb Human genes 0.000 description 5
- 102100037208 Zinc finger protein basonuclin-2 Human genes 0.000 description 5
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 description 5
- 125000003275 alpha amino acid group Chemical group 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 208000005017 glioblastoma Diseases 0.000 description 5
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 102100022454 Actin, gamma-enteric smooth muscle Human genes 0.000 description 4
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 4
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 4
- 102100030010 Calpain-7 Human genes 0.000 description 4
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 4
- 102100036943 Cytoplasmic protein NCK1 Human genes 0.000 description 4
- 108010086291 Deubiquitinating Enzyme CYLD Proteins 0.000 description 4
- 102100040465 Elongation factor 1-beta Human genes 0.000 description 4
- 102100036448 Endothelial PAS domain-containing protein 1 Human genes 0.000 description 4
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 4
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 4
- 101000888214 Flaveria pringlei Serine hydroxymethyltransferase 1, mitochondrial Proteins 0.000 description 4
- 102100022148 G protein pathway suppressor 2 Human genes 0.000 description 4
- 102100023941 G-protein-signaling modulator 2 Human genes 0.000 description 4
- 102100027541 GTP-binding protein Rheb Human genes 0.000 description 4
- 102100034155 Guanine nucleotide-binding protein G(i) subunit alpha-1 Human genes 0.000 description 4
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 4
- 102100021455 Histone deacetylase 3 Human genes 0.000 description 4
- 102100023584 Histone-binding protein RBBP7 Human genes 0.000 description 4
- 101000751611 Homo sapiens ADP-ribosylation factor GTPase-activating protein 1 Proteins 0.000 description 4
- 101000678433 Homo sapiens Actin, gamma-enteric smooth muscle Proteins 0.000 description 4
- 101000793684 Homo sapiens Calpain-7 Proteins 0.000 description 4
- 101001024707 Homo sapiens Cytoplasmic protein NCK1 Proteins 0.000 description 4
- 101000967447 Homo sapiens Elongation factor 1-beta Proteins 0.000 description 4
- 101000900320 Homo sapiens G protein pathway suppressor 2 Proteins 0.000 description 4
- 101000904754 Homo sapiens G-protein-signaling modulator 2 Proteins 0.000 description 4
- 101001070526 Homo sapiens Guanine nucleotide-binding protein G(i) subunit alpha-1 Proteins 0.000 description 4
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 4
- 101000899282 Homo sapiens Histone deacetylase 3 Proteins 0.000 description 4
- 101000599886 Homo sapiens Isocitrate dehydrogenase [NADP], mitochondrial Proteins 0.000 description 4
- 101001133091 Homo sapiens Mucin-20 Proteins 0.000 description 4
- 101000580092 Homo sapiens RNA-binding protein 10 Proteins 0.000 description 4
- 101000579226 Homo sapiens Renin receptor Proteins 0.000 description 4
- 101001040808 Homo sapiens Serine hydroxymethyltransferase, cytosolic Proteins 0.000 description 4
- 101000628562 Homo sapiens Serine/threonine-protein kinase STK11 Proteins 0.000 description 4
- 101000783373 Homo sapiens Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform Proteins 0.000 description 4
- 101000808799 Homo sapiens Splicing factor U2AF 35 kDa subunit Proteins 0.000 description 4
- 101000662534 Homo sapiens Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 Proteins 0.000 description 4
- 101000798942 Homo sapiens Target of Myb protein 1 Proteins 0.000 description 4
- 101000823782 Homo sapiens Y-box-binding protein 3 Proteins 0.000 description 4
- 102100037845 Isocitrate dehydrogenase [NADP], mitochondrial Human genes 0.000 description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 4
- 102100034242 Mucin-20 Human genes 0.000 description 4
- 108010047613 PTB-Associated Splicing Factor Proteins 0.000 description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 4
- 101150020518 RHEB gene Proteins 0.000 description 4
- 102100027514 RNA-binding protein 10 Human genes 0.000 description 4
- 102100028254 Renin receptor Human genes 0.000 description 4
- 108010071000 Retinoblastoma-Binding Protein 7 Proteins 0.000 description 4
- 102100021225 Serine hydroxymethyltransferase, cytosolic Human genes 0.000 description 4
- 102100026715 Serine/threonine-protein kinase STK11 Human genes 0.000 description 4
- 102100036140 Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform Human genes 0.000 description 4
- 102100038501 Splicing factor U2AF 35 kDa subunit Human genes 0.000 description 4
- 102100027780 Splicing factor, proline- and glutamine-rich Human genes 0.000 description 4
- 102100037409 Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 Human genes 0.000 description 4
- 102100034024 Target of Myb protein 1 Human genes 0.000 description 4
- 102100024250 Ubiquitin carboxyl-terminal hydrolase CYLD Human genes 0.000 description 4
- 102100022221 Y-box-binding protein 3 Human genes 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 4
- 108010018033 endothelial PAS domain-containing protein 1 Proteins 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000037432 silent mutation Effects 0.000 description 4
- 208000000587 small cell lung carcinoma Diseases 0.000 description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 4
- 102100022089 Acyl-[acyl-carrier-protein] hydrolase Human genes 0.000 description 3
- 102100027314 Beta-2-microglobulin Human genes 0.000 description 3
- 101000964894 Bos taurus 14-3-3 protein zeta/delta Proteins 0.000 description 3
- 108010060313 Core Binding Factor beta Subunit Proteins 0.000 description 3
- 102000008147 Core Binding Factor beta Subunit Human genes 0.000 description 3
- 108010016788 Cyclin-Dependent Kinase Inhibitor p21 Proteins 0.000 description 3
- 102100033270 Cyclin-dependent kinase inhibitor 1 Human genes 0.000 description 3
- 102210042925 HLA-A*02:01 Human genes 0.000 description 3
- 102100038720 Histone deacetylase 9 Human genes 0.000 description 3
- 101000824278 Homo sapiens Acyl-[acyl-carrier-protein] hydrolase Proteins 0.000 description 3
- 101000937544 Homo sapiens Beta-2-microglobulin Proteins 0.000 description 3
- 101001032092 Homo sapiens Histone deacetylase 9 Proteins 0.000 description 3
- 101001090713 Homo sapiens L-lactate dehydrogenase A chain Proteins 0.000 description 3
- 101001000104 Homo sapiens Myosin-11 Proteins 0.000 description 3
- 101001030232 Homo sapiens Myosin-9 Proteins 0.000 description 3
- 101001109719 Homo sapiens Nucleophosmin Proteins 0.000 description 3
- 101000974015 Homo sapiens Nucleosome assembly protein 1-like 1 Proteins 0.000 description 3
- 101001090813 Homo sapiens Proteasome subunit alpha type-6 Proteins 0.000 description 3
- 101000785887 Homo sapiens Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform Proteins 0.000 description 3
- 101000707569 Homo sapiens Splicing factor 3A subunit 3 Proteins 0.000 description 3
- 101000666385 Homo sapiens Transcription factor Dp-2 Proteins 0.000 description 3
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 3
- 101000717424 Homo sapiens UV excision repair protein RAD23 homolog B Proteins 0.000 description 3
- 102100034671 L-lactate dehydrogenase A chain Human genes 0.000 description 3
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 3
- 102100036639 Myosin-11 Human genes 0.000 description 3
- 102100038938 Myosin-9 Human genes 0.000 description 3
- 102100025246 Neurogenic locus notch homolog protein 2 Human genes 0.000 description 3
- 108010029751 Notch2 Receptor Proteins 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 102100022678 Nucleophosmin Human genes 0.000 description 3
- 102100022389 Nucleosome assembly protein 1-like 1 Human genes 0.000 description 3
- 102100034664 Proteasome subunit alpha type-6 Human genes 0.000 description 3
- 102000003890 RNA-binding protein FUS Human genes 0.000 description 3
- 108090000292 RNA-binding protein FUS Proteins 0.000 description 3
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 3
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 3
- 102100026282 Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform Human genes 0.000 description 3
- 102100031710 Splicing factor 3A subunit 3 Human genes 0.000 description 3
- 102100038312 Transcription factor Dp-2 Human genes 0.000 description 3
- 101150013568 US16 gene Proteins 0.000 description 3
- 102100020779 UV excision repair protein RAD23 homolog B Human genes 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000010205 computational analysis Methods 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 238000003205 genotyping method Methods 0.000 description 3
- 238000002552 multiple reaction monitoring Methods 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- 102100030390 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 Human genes 0.000 description 2
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 2
- 108700020462 BRCA2 Proteins 0.000 description 2
- 102000052609 BRCA2 Human genes 0.000 description 2
- 101150008921 Brca2 gene Proteins 0.000 description 2
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 102100035910 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 Human genes 0.000 description 2
- 102100028971 HLA class I histocompatibility antigen, C alpha chain Human genes 0.000 description 2
- 108010052199 HLA-C Antigens Proteins 0.000 description 2
- 102100029235 Histone-lysine N-methyltransferase NSD3 Human genes 0.000 description 2
- 101000583063 Homo sapiens 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 Proteins 0.000 description 2
- 101000779641 Homo sapiens ALK tyrosine kinase receptor Proteins 0.000 description 2
- 101001073272 Homo sapiens Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 Proteins 0.000 description 2
- 101000634046 Homo sapiens Histone-lysine N-methyltransferase NSD3 Proteins 0.000 description 2
- 101001011393 Homo sapiens Interferon regulatory factor 2 Proteins 0.000 description 2
- 101001090928 Homo sapiens Regulator of nonsense transcripts 3B Proteins 0.000 description 2
- 101000702545 Homo sapiens Transcription activator BRG1 Proteins 0.000 description 2
- 101000744900 Homo sapiens Zinc finger homeobox protein 3 Proteins 0.000 description 2
- 101001026573 Homo sapiens cAMP-dependent protein kinase type I-alpha regulatory subunit Proteins 0.000 description 2
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 2
- 102100029838 Interferon regulatory factor 2 Human genes 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 108010021466 Mutant Proteins Proteins 0.000 description 2
- 102000008300 Mutant Proteins Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 102100022122 Ras-related C3 botulinum toxin substrate 1 Human genes 0.000 description 2
- 102100037415 Regulator of G-protein signaling 3 Human genes 0.000 description 2
- 101710140411 Regulator of G-protein signaling 3 Proteins 0.000 description 2
- 102100034978 Regulator of nonsense transcripts 3B Human genes 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 102100031027 Transcription activator BRG1 Human genes 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- 108091002437 YBX1 Proteins 0.000 description 2
- 102000033021 YBX1 Human genes 0.000 description 2
- 102100039966 Zinc finger homeobox protein 3 Human genes 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 102100037490 cAMP-dependent protein kinase type I-alpha regulatory subunit Human genes 0.000 description 2
- 238000009566 cancer vaccine Methods 0.000 description 2
- 229940022399 cancer vaccine Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 230000037433 frameshift Effects 0.000 description 2
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 2
- 230000007762 localization of cell Effects 0.000 description 2
- 208000030173 low grade glioma Diseases 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000003032 molecular docking Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000009437 off-target effect Effects 0.000 description 2
- 239000013610 patient sample Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 108010062302 rac1 GTP Binding Protein Proteins 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000004797 therapeutic response Effects 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- 102100026205 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 Human genes 0.000 description 1
- 102100039583 116 kDa U5 small nuclear ribonucleoprotein component Human genes 0.000 description 1
- FDFPSNISSMYYDS-UHFFFAOYSA-N 2-ethyl-N,2-dimethylheptanamide Chemical compound CCCCCC(C)(CC)C(=O)NC FDFPSNISSMYYDS-UHFFFAOYSA-N 0.000 description 1
- 102100040964 26S proteasome non-ATPase regulatory subunit 11 Human genes 0.000 description 1
- 102100036962 5'-3' exoribonuclease 1 Human genes 0.000 description 1
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 1
- 102100030841 AT-rich interactive domain-containing protein 4A Human genes 0.000 description 1
- 102100030840 AT-rich interactive domain-containing protein 4B Human genes 0.000 description 1
- 102100030835 AT-rich interactive domain-containing protein 5B Human genes 0.000 description 1
- 102100030088 ATP-dependent RNA helicase A Human genes 0.000 description 1
- 102100039164 Acetyl-CoA carboxylase 1 Human genes 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 102100039677 Adenylate cyclase type 1 Human genes 0.000 description 1
- 102100036775 Afadin Human genes 0.000 description 1
- 102100027211 Albumin Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 241000710929 Alphavirus Species 0.000 description 1
- 102000052587 Anaphase-Promoting Complex-Cyclosome Apc3 Subunit Human genes 0.000 description 1
- 108700004606 Anaphase-Promoting Complex-Cyclosome Apc3 Subunit Proteins 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 102100034524 Apoptotic protease-activating factor 1 Human genes 0.000 description 1
- 102100033648 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 Human genes 0.000 description 1
- 102100035682 Axin-1 Human genes 0.000 description 1
- 102100035683 Axin-2 Human genes 0.000 description 1
- 102100022976 B-cell lymphoma/leukemia 11A Human genes 0.000 description 1
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 description 1
- 102100025616 Beta-1,3-N-acetylglucosaminyltransferase manic fringe Human genes 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102100025994 Brefeldin A-inhibited guanine nucleotide-exchange protein 1 Human genes 0.000 description 1
- 101710098191 C-4 methylsterol oxidase ERG25 Proteins 0.000 description 1
- 102100034808 CCAAT/enhancer-binding protein alpha Human genes 0.000 description 1
- 101150108242 CDC27 gene Proteins 0.000 description 1
- 102100040755 CREB-regulated transcription coactivator 3 Human genes 0.000 description 1
- 102100040751 Casein kinase II subunit alpha Human genes 0.000 description 1
- 102100028906 Catenin delta-1 Human genes 0.000 description 1
- 102100028633 Cdc42-interacting protein 4 Human genes 0.000 description 1
- 102100029397 Chloride channel CLIC-like protein 1 Human genes 0.000 description 1
- 102100038220 Chromodomain-helicase-DNA-binding protein 6 Human genes 0.000 description 1
- 102100038165 Chromodomain-helicase-DNA-binding protein 8 Human genes 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 description 1
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- 102100040501 Contactin-associated protein 1 Human genes 0.000 description 1
- 102100032182 Crooked neck-like protein 1 Human genes 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 102100025843 Cytohesin-4 Human genes 0.000 description 1
- 102100037810 DEP domain-containing protein 1B Human genes 0.000 description 1
- 102100038826 DNA helicase MCM8 Human genes 0.000 description 1
- 102100028849 DNA mismatch repair protein Mlh3 Human genes 0.000 description 1
- 102100039606 DNA replication licensing factor MCM3 Human genes 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 101100216227 Dictyostelium discoideum anapc3 gene Proteins 0.000 description 1
- 102100031648 Dynein axonemal heavy chain 5 Human genes 0.000 description 1
- 101710201734 E3 protein Proteins 0.000 description 1
- 102100038662 E3 ubiquitin-protein ligase SMURF2 Human genes 0.000 description 1
- 101150076616 EPHA2 gene Proteins 0.000 description 1
- 101150097734 EPHB2 gene Proteins 0.000 description 1
- 102100039247 ETS-related transcription factor Elf-4 Human genes 0.000 description 1
- 208000005431 Endometrioid Carcinoma Diseases 0.000 description 1
- 102100031948 Enhancer of polycomb homolog 1 Human genes 0.000 description 1
- 108010055211 EphA1 Receptor Proteins 0.000 description 1
- 101150078651 Epha4 gene Proteins 0.000 description 1
- 102100030322 Ephrin type-A receptor 1 Human genes 0.000 description 1
- 102100030340 Ephrin type-A receptor 2 Human genes 0.000 description 1
- 102100021616 Ephrin type-A receptor 4 Human genes 0.000 description 1
- 102100031968 Ephrin type-B receptor 2 Human genes 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 102100040022 Eukaryotic translation initiation factor 4 gamma 3 Human genes 0.000 description 1
- 102100029095 Exportin-1 Human genes 0.000 description 1
- 102100038578 F-box only protein 11 Human genes 0.000 description 1
- 102100027279 FAS-associated factor 1 Human genes 0.000 description 1
- 102100034554 Fanconi anemia group I protein Human genes 0.000 description 1
- 102100034334 Fatty acid CoA ligase Acsl3 Human genes 0.000 description 1
- 102100031513 Fc receptor-like protein 4 Human genes 0.000 description 1
- 102100024165 G1/S-specific cyclin-D1 Human genes 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102100036738 Guanine nucleotide-binding protein subunit alpha-11 Human genes 0.000 description 1
- 102100040485 HLA class II histocompatibility antigen, DRB1 beta chain Human genes 0.000 description 1
- 108010010378 HLA-DP Antigens Proteins 0.000 description 1
- 102000015789 HLA-DP Antigens Human genes 0.000 description 1
- 108010062347 HLA-DQ Antigens Proteins 0.000 description 1
- 108010058597 HLA-DR Antigens Proteins 0.000 description 1
- 102000006354 HLA-DR Antigens Human genes 0.000 description 1
- 108010039343 HLA-DRB1 Chains Proteins 0.000 description 1
- 102100031561 Hamartin Human genes 0.000 description 1
- 102100022057 Hepatocyte nuclear factor 1-alpha Human genes 0.000 description 1
- 102100029283 Hepatocyte nuclear factor 3-alpha Human genes 0.000 description 1
- 102100029284 Hepatocyte nuclear factor 3-beta Human genes 0.000 description 1
- 102100033070 Histone acetyltransferase KAT6B Human genes 0.000 description 1
- 102100029234 Histone-lysine N-methyltransferase NSD2 Human genes 0.000 description 1
- 102100028092 Homeobox protein Nkx-3.1 Human genes 0.000 description 1
- 102100030234 Homeobox protein cut-like 1 Human genes 0.000 description 1
- 101000691599 Homo sapiens 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 Proteins 0.000 description 1
- 101000608799 Homo sapiens 116 kDa U5 small nuclear ribonucleoprotein component Proteins 0.000 description 1
- 101000612519 Homo sapiens 26S proteasome non-ATPase regulatory subunit 11 Proteins 0.000 description 1
- 101000804879 Homo sapiens 5'-3' exoribonuclease 1 Proteins 0.000 description 1
- 101000627872 Homo sapiens 72 kDa type IV collagenase Proteins 0.000 description 1
- 101000792933 Homo sapiens AT-rich interactive domain-containing protein 4A Proteins 0.000 description 1
- 101000792935 Homo sapiens AT-rich interactive domain-containing protein 4B Proteins 0.000 description 1
- 101000792947 Homo sapiens AT-rich interactive domain-containing protein 5B Proteins 0.000 description 1
- 101000864670 Homo sapiens ATP-dependent RNA helicase A Proteins 0.000 description 1
- 101000963424 Homo sapiens Acetyl-CoA carboxylase 1 Proteins 0.000 description 1
- 101000959343 Homo sapiens Adenylate cyclase type 1 Proteins 0.000 description 1
- 101000928246 Homo sapiens Afadin Proteins 0.000 description 1
- 101000924629 Homo sapiens Apoptotic protease-activating factor 1 Proteins 0.000 description 1
- 101000733571 Homo sapiens Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 Proteins 0.000 description 1
- 101000874566 Homo sapiens Axin-1 Proteins 0.000 description 1
- 101000874569 Homo sapiens Axin-2 Proteins 0.000 description 1
- 101000903703 Homo sapiens B-cell lymphoma/leukemia 11A Proteins 0.000 description 1
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 description 1
- 101000575420 Homo sapiens Beta-1,3-N-acetylglucosaminyltransferase manic fringe Proteins 0.000 description 1
- 101000933371 Homo sapiens Brefeldin A-inhibited guanine nucleotide-exchange protein 1 Proteins 0.000 description 1
- 101000945515 Homo sapiens CCAAT/enhancer-binding protein alpha Proteins 0.000 description 1
- 101100382122 Homo sapiens CIITA gene Proteins 0.000 description 1
- 101000891906 Homo sapiens CREB-regulated transcription coactivator 3 Proteins 0.000 description 1
- 101000892026 Homo sapiens Casein kinase II subunit alpha Proteins 0.000 description 1
- 101000892015 Homo sapiens Casein kinase II subunit alpha' Proteins 0.000 description 1
- 101000916264 Homo sapiens Catenin delta-1 Proteins 0.000 description 1
- 101000766830 Homo sapiens Cdc42-interacting protein 4 Proteins 0.000 description 1
- 101000989992 Homo sapiens Chloride channel CLIC-like protein 1 Proteins 0.000 description 1
- 101000883736 Homo sapiens Chromodomain-helicase-DNA-binding protein 6 Proteins 0.000 description 1
- 101000883545 Homo sapiens Chromodomain-helicase-DNA-binding protein 8 Proteins 0.000 description 1
- 101000749872 Homo sapiens Contactin-associated protein 1 Proteins 0.000 description 1
- 101000921063 Homo sapiens Crooked neck-like protein 1 Proteins 0.000 description 1
- 101000855828 Homo sapiens Cytohesin-4 Proteins 0.000 description 1
- 101000950656 Homo sapiens DEP domain-containing protein 1B Proteins 0.000 description 1
- 101000957174 Homo sapiens DNA helicase MCM8 Proteins 0.000 description 1
- 101000577867 Homo sapiens DNA mismatch repair protein Mlh3 Proteins 0.000 description 1
- 101000963174 Homo sapiens DNA replication licensing factor MCM3 Proteins 0.000 description 1
- 101000664952 Homo sapiens E3 ubiquitin-protein ligase SMURF2 Proteins 0.000 description 1
- 101000813135 Homo sapiens ETS-related transcription factor Elf-4 Proteins 0.000 description 1
- 101000920634 Homo sapiens Enhancer of polycomb homolog 1 Proteins 0.000 description 1
- 101001034840 Homo sapiens Eukaryotic translation initiation factor 4 gamma 3 Proteins 0.000 description 1
- 101001030683 Homo sapiens F-box only protein 11 Proteins 0.000 description 1
- 101000914654 Homo sapiens FAS-associated factor 1 Proteins 0.000 description 1
- 101000848174 Homo sapiens Fanconi anemia group I protein Proteins 0.000 description 1
- 101000780194 Homo sapiens Fatty acid CoA ligase Acsl3 Proteins 0.000 description 1
- 101000846909 Homo sapiens Fc receptor-like protein 4 Proteins 0.000 description 1
- 101001072407 Homo sapiens Guanine nucleotide-binding protein subunit alpha-11 Proteins 0.000 description 1
- 101000795643 Homo sapiens Hamartin Proteins 0.000 description 1
- 101001045751 Homo sapiens Hepatocyte nuclear factor 1-alpha Proteins 0.000 description 1
- 101001062353 Homo sapiens Hepatocyte nuclear factor 3-alpha Proteins 0.000 description 1
- 101001062347 Homo sapiens Hepatocyte nuclear factor 3-beta Proteins 0.000 description 1
- 101000944174 Homo sapiens Histone acetyltransferase KAT6B Proteins 0.000 description 1
- 101000634048 Homo sapiens Histone-lysine N-methyltransferase NSD2 Proteins 0.000 description 1
- 101000578249 Homo sapiens Homeobox protein Nkx-3.1 Proteins 0.000 description 1
- 101000726740 Homo sapiens Homeobox protein cut-like 1 Proteins 0.000 description 1
- 101001053362 Homo sapiens Inositol polyphosphate-4-phosphatase type I A Proteins 0.000 description 1
- 101001011446 Homo sapiens Interferon regulatory factor 6 Proteins 0.000 description 1
- 101001032342 Homo sapiens Interferon regulatory factor 7 Proteins 0.000 description 1
- 101000975528 Homo sapiens Junction-mediating and -regulatory protein Proteins 0.000 description 1
- 101001134694 Homo sapiens LIM domain and actin-binding protein 1 Proteins 0.000 description 1
- 101000972491 Homo sapiens Laminin subunit alpha-2 Proteins 0.000 description 1
- 101000966742 Homo sapiens Leucine-rich PPR motif-containing protein, mitochondrial Proteins 0.000 description 1
- 101001137975 Homo sapiens Leucyl-cystinyl aminopeptidase Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101001019117 Homo sapiens Mediator of RNA polymerase II transcription subunit 23 Proteins 0.000 description 1
- 101000578932 Homo sapiens Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 Proteins 0.000 description 1
- 101000653374 Homo sapiens Methylcytosine dioxygenase TET2 Proteins 0.000 description 1
- 101000990982 Homo sapiens Mitochondrial Rho GTPase 1 Proteins 0.000 description 1
- 101001005602 Homo sapiens Mitogen-activated protein kinase kinase kinase 11 Proteins 0.000 description 1
- 101001059991 Homo sapiens Mitogen-activated protein kinase kinase kinase kinase 1 Proteins 0.000 description 1
- 101001030211 Homo sapiens Myc proto-oncogene protein Proteins 0.000 description 1
- 101000577891 Homo sapiens Myeloid cell nuclear differentiation antigen Proteins 0.000 description 1
- 101000588964 Homo sapiens Myosin-14 Proteins 0.000 description 1
- 101000958744 Homo sapiens Myosin-7B Proteins 0.000 description 1
- 101001122114 Homo sapiens NUT family member 1 Proteins 0.000 description 1
- 101001121613 Homo sapiens Nuclear envelope pore membrane protein POM 121 Proteins 0.000 description 1
- 101001007909 Homo sapiens Nuclear pore complex protein Nup93 Proteins 0.000 description 1
- 101000582254 Homo sapiens Nuclear receptor corepressor 2 Proteins 0.000 description 1
- 101000736088 Homo sapiens PC4 and SFRS1-interacting protein Proteins 0.000 description 1
- 101001095329 Homo sapiens POM121 and ZP3 fusion protein Proteins 0.000 description 1
- 101000878253 Homo sapiens Peptidyl-prolyl cis-trans isomerase FKBP5 Proteins 0.000 description 1
- 101000579484 Homo sapiens Period circadian protein homolog 1 Proteins 0.000 description 1
- 101000688606 Homo sapiens Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 Proteins 0.000 description 1
- 101000721645 Homo sapiens Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta Proteins 0.000 description 1
- 101001067189 Homo sapiens Plexin-A1 Proteins 0.000 description 1
- 101001067170 Homo sapiens Plexin-B2 Proteins 0.000 description 1
- 101000735354 Homo sapiens Poly(rC)-binding protein 1 Proteins 0.000 description 1
- 101000609215 Homo sapiens Polyadenylate-binding protein 3 Proteins 0.000 description 1
- 101000728236 Homo sapiens Polycomb group protein ASXL1 Proteins 0.000 description 1
- 101001126582 Homo sapiens Post-GPI attachment to proteins factor 3 Proteins 0.000 description 1
- 101000846284 Homo sapiens Pre-mRNA 3'-end-processing factor FIP1 Proteins 0.000 description 1
- 101000901928 Homo sapiens Probable ATP-dependent RNA helicase DHX35 Proteins 0.000 description 1
- 101000702560 Homo sapiens Probable global transcription activator SNF2L1 Proteins 0.000 description 1
- 101001072081 Homo sapiens Proprotein convertase subtilisin/kexin type 5 Proteins 0.000 description 1
- 101000705766 Homo sapiens Proteasome activator complex subunit 3 Proteins 0.000 description 1
- 101000761460 Homo sapiens Protein CASP Proteins 0.000 description 1
- 101000881752 Homo sapiens Protein ELYS Proteins 0.000 description 1
- 101001061041 Homo sapiens Protein FRG1 Proteins 0.000 description 1
- 101000740224 Homo sapiens Protein SCAI Proteins 0.000 description 1
- 101000804792 Homo sapiens Protein Wnt-5a Proteins 0.000 description 1
- 101000971468 Homo sapiens Protein kinase C zeta type Proteins 0.000 description 1
- 101000742054 Homo sapiens Protein phosphatase 1D Proteins 0.000 description 1
- 101000822459 Homo sapiens Protein transport protein Sec31A Proteins 0.000 description 1
- 101000824299 Homo sapiens Protocadherin Fat 2 Proteins 0.000 description 1
- 101001069891 Homo sapiens RAS guanyl-releasing protein 1 Proteins 0.000 description 1
- 101001130505 Homo sapiens Ras GTPase-activating protein 2 Proteins 0.000 description 1
- 101000893689 Homo sapiens Ras GTPase-activating protein-binding protein 1 Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000606545 Homo sapiens Receptor-type tyrosine-protein phosphatase F Proteins 0.000 description 1
- 101000582404 Homo sapiens Replication factor C subunit 4 Proteins 0.000 description 1
- 101001075558 Homo sapiens Rho GTPase-activating protein 29 Proteins 0.000 description 1
- 101000752221 Homo sapiens Rho guanine nucleotide exchange factor 2 Proteins 0.000 description 1
- 101000650697 Homo sapiens Roundabout homolog 2 Proteins 0.000 description 1
- 101000947881 Homo sapiens S-adenosylmethionine synthase isoform type-2 Proteins 0.000 description 1
- 101000616523 Homo sapiens SH2B adapter protein 3 Proteins 0.000 description 1
- 101100311211 Homo sapiens STARD13 gene Proteins 0.000 description 1
- 101000770770 Homo sapiens Serine/threonine-protein kinase WNK1 Proteins 0.000 description 1
- 101000620662 Homo sapiens Serine/threonine-protein phosphatase 6 catalytic subunit Proteins 0.000 description 1
- 101000663568 Homo sapiens Small proline-rich protein 3 Proteins 0.000 description 1
- 101000829367 Homo sapiens Src substrate cortactin Proteins 0.000 description 1
- 101000666429 Homo sapiens Terminal nucleotidyltransferase 5C Proteins 0.000 description 1
- 101000796022 Homo sapiens Thioredoxin-interacting protein Proteins 0.000 description 1
- 101000652324 Homo sapiens Transcription factor SOX-17 Proteins 0.000 description 1
- 101000634900 Homo sapiens Transcriptional-regulating factor 1 Proteins 0.000 description 1
- 101000648495 Homo sapiens Transportin-2 Proteins 0.000 description 1
- 101000823271 Homo sapiens Tyrosine-protein kinase ABL2 Proteins 0.000 description 1
- 101000604583 Homo sapiens Tyrosine-protein kinase SYK Proteins 0.000 description 1
- 101000643895 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 6 Proteins 0.000 description 1
- 101000803403 Homo sapiens Vimentin Proteins 0.000 description 1
- 101001104102 Homo sapiens X-linked retinitis pigmentosa GTPase regulator Proteins 0.000 description 1
- 101000723902 Homo sapiens Zinc finger protein 292 Proteins 0.000 description 1
- 101000802329 Homo sapiens Zinc finger protein 750 Proteins 0.000 description 1
- 101000802094 Homo sapiens mRNA decay activator protein ZFP36L1 Proteins 0.000 description 1
- 108010027310 Host Cell Factor C1 Proteins 0.000 description 1
- 102100030355 Host cell factor 1 Human genes 0.000 description 1
- 102000003781 Inhibitor of growth protein 1 Human genes 0.000 description 1
- 108090000191 Inhibitor of growth protein 1 Proteins 0.000 description 1
- 102100024367 Inositol polyphosphate-4-phosphatase type I A Human genes 0.000 description 1
- 102100030130 Interferon regulatory factor 6 Human genes 0.000 description 1
- 102100038070 Interferon regulatory factor 7 Human genes 0.000 description 1
- 102100023956 Junction-mediating and -regulatory protein Human genes 0.000 description 1
- 102100033339 LIM domain and actin-binding protein 1 Human genes 0.000 description 1
- 102100022745 Laminin subunit alpha-2 Human genes 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 102100040589 Leucine-rich PPR motif-containing protein, mitochondrial Human genes 0.000 description 1
- 102100020872 Leucyl-cystinyl aminopeptidase Human genes 0.000 description 1
- 108010018650 MEF2 Transcription Factors Proteins 0.000 description 1
- 102100026371 MHC class II transactivator Human genes 0.000 description 1
- 108700002010 MHC class II transactivator Proteins 0.000 description 1
- 108700012912 MYCN Proteins 0.000 description 1
- 101150022024 MYCN gene Proteins 0.000 description 1
- 101150053046 MYD88 gene Proteins 0.000 description 1
- 102100034771 Mediator of RNA polymerase II transcription subunit 23 Human genes 0.000 description 1
- 102100028328 Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 Human genes 0.000 description 1
- 102100025825 Methylated-DNA-protein-cysteine methyltransferase Human genes 0.000 description 1
- 102100030803 Methylcytosine dioxygenase TET2 Human genes 0.000 description 1
- 102100030331 Mitochondrial Rho GTPase 1 Human genes 0.000 description 1
- 102100025207 Mitogen-activated protein kinase kinase kinase 11 Human genes 0.000 description 1
- 102100028199 Mitogen-activated protein kinase kinase kinase kinase 1 Human genes 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- 102100027994 Myeloid cell nuclear differentiation antigen Human genes 0.000 description 1
- 102100024134 Myeloid differentiation primary response protein MyD88 Human genes 0.000 description 1
- 102100039229 Myocyte-specific enhancer factor 2C Human genes 0.000 description 1
- 102100032972 Myosin-14 Human genes 0.000 description 1
- 108700026495 N-Myc Proto-Oncogene Proteins 0.000 description 1
- 102100030124 N-myc proto-oncogene protein Human genes 0.000 description 1
- 102100027086 NUT family member 1 Human genes 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 108020004485 Nonsense Codon Proteins 0.000 description 1
- 102100025812 Nuclear envelope pore membrane protein POM 121 Human genes 0.000 description 1
- 102100027585 Nuclear pore complex protein Nup93 Human genes 0.000 description 1
- 102100030569 Nuclear receptor corepressor 2 Human genes 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102100036220 PC4 and SFRS1-interacting protein Human genes 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108010065129 Patched-1 Receptor Proteins 0.000 description 1
- 102000012850 Patched-1 Receptor Human genes 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 102100037026 Peptidyl-prolyl cis-trans isomerase FKBP5 Human genes 0.000 description 1
- 102100028293 Period circadian protein homolog 1 Human genes 0.000 description 1
- 102100024242 Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 Human genes 0.000 description 1
- 102100025059 Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta Human genes 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102100034382 Plexin-A1 Human genes 0.000 description 1
- 102100034383 Plexin-B2 Human genes 0.000 description 1
- 108010012887 Poly(A)-Binding Protein I Proteins 0.000 description 1
- 102100034960 Poly(rC)-binding protein 1 Human genes 0.000 description 1
- 102100026090 Polyadenylate-binding protein 1 Human genes 0.000 description 1
- 102100039425 Polyadenylate-binding protein 3 Human genes 0.000 description 1
- 102100029799 Polycomb group protein ASXL1 Human genes 0.000 description 1
- 102100031755 Pre-mRNA 3'-end-processing factor FIP1 Human genes 0.000 description 1
- 102100022424 Probable ATP-dependent RNA helicase DHX35 Human genes 0.000 description 1
- 102100031031 Probable global transcription activator SNF2L1 Human genes 0.000 description 1
- 102100036365 Proprotein convertase subtilisin/kexin type 5 Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102100031298 Proteasome activator complex subunit 3 Human genes 0.000 description 1
- 102100037113 Protein ELYS Human genes 0.000 description 1
- 102100028387 Protein FRG1 Human genes 0.000 description 1
- 102220484827 Protein NDRG1_N3A_mutation Human genes 0.000 description 1
- 102100037197 Protein SCAI Human genes 0.000 description 1
- 102100021538 Protein kinase C zeta type Human genes 0.000 description 1
- 102100038675 Protein phosphatase 1D Human genes 0.000 description 1
- 102100022484 Protein transport protein Sec31A Human genes 0.000 description 1
- 102100022093 Protocadherin Fat 2 Human genes 0.000 description 1
- 101710184733 Pterin-4-alpha-carbinolamine dehydratase Proteins 0.000 description 1
- 101710201301 Putative pterin-4-alpha-carbinolamine dehydratase Proteins 0.000 description 1
- 102100034220 RAS guanyl-releasing protein 1 Human genes 0.000 description 1
- 238000013381 RNA quantification Methods 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 102100031427 Ras GTPase-activating protein 2 Human genes 0.000 description 1
- 102100040854 Ras GTPase-activating protein-binding protein 1 Human genes 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 102100039663 Receptor-type tyrosine-protein phosphatase F Human genes 0.000 description 1
- 108700005075 Regulator Genes Proteins 0.000 description 1
- 102100030542 Replication factor C subunit 4 Human genes 0.000 description 1
- 102100020899 Rho GTPase-activating protein 29 Human genes 0.000 description 1
- 102100021707 Rho guanine nucleotide exchange factor 2 Human genes 0.000 description 1
- 102100027739 Roundabout homolog 2 Human genes 0.000 description 1
- 102100035947 S-adenosylmethionine synthase isoform type-2 Human genes 0.000 description 1
- 102100021778 SH2B adapter protein 3 Human genes 0.000 description 1
- 102100037356 SLIT-ROBO Rho GTPase-activating protein 1 Human genes 0.000 description 1
- 108700028341 SMARCB1 Proteins 0.000 description 1
- 101150008214 SMARCB1 gene Proteins 0.000 description 1
- 102100025746 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 Human genes 0.000 description 1
- 101100485284 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CRM1 gene Proteins 0.000 description 1
- 102100029064 Serine/threonine-protein kinase WNK1 Human genes 0.000 description 1
- 102100022345 Serine/threonine-protein phosphatase 6 catalytic subunit Human genes 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 102100038979 Small proline-rich protein 3 Human genes 0.000 description 1
- 102000013380 Smoothened Receptor Human genes 0.000 description 1
- 101710090597 Smoothened homolog Proteins 0.000 description 1
- 102100023719 Src substrate cortactin Human genes 0.000 description 1
- 101150066728 Srgap1 gene Proteins 0.000 description 1
- 102100025252 StAR-related lipid transfer protein 13 Human genes 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 102100038305 Terminal nucleotidyltransferase 5C Human genes 0.000 description 1
- 102100031344 Thioredoxin-interacting protein Human genes 0.000 description 1
- 102100030243 Transcription factor SOX-17 Human genes 0.000 description 1
- 102100029446 Transcriptional-regulating factor 1 Human genes 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 102100028747 Transportin-2 Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 102100022651 Tyrosine-protein kinase ABL2 Human genes 0.000 description 1
- 102100038183 Tyrosine-protein kinase SYK Human genes 0.000 description 1
- 102100021015 Ubiquitin carboxyl-terminal hydrolase 6 Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 102100035071 Vimentin Human genes 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 108010062653 Wiskott-Aldrich Syndrome Protein Family Proteins 0.000 description 1
- 102100037104 Wiskott-Aldrich syndrome protein family member 3 Human genes 0.000 description 1
- 102000043366 Wnt-5a Human genes 0.000 description 1
- 102100040092 X-linked retinitis pigmentosa GTPase regulator Human genes 0.000 description 1
- 101150094313 XPO1 gene Proteins 0.000 description 1
- 102100028431 Zinc finger protein 292 Human genes 0.000 description 1
- 102100034644 Zinc finger protein 750 Human genes 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000012482 calibration solution Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 239000000571 coke Substances 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 208000030381 cutaneous melanoma Diseases 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 238000013500 data storage Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000037437 driver mutation Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 208000028730 endometrioid adenocarcinoma Diseases 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 108700002148 exportin 1 Proteins 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000007672 fourth generation sequencing Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000002998 immunogenetic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 1
- 102100034702 mRNA decay activator protein ZFP36L1 Human genes 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 108040008770 methylated-DNA-[protein]-cysteine S-methyltransferase activity proteins Proteins 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 210000000276 neural tube Anatomy 0.000 description 1
- 230000037434 nonsense mutation Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000003068 pathway analysis Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 238000000734 protein sequencing Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 201000003708 skin melanoma Diseases 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000005082 stem growth Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000011191 terminal modification Methods 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000007704 wet chemistry method Methods 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6881—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for tissue or cell typing, e.g. human leukocyte antigen [HLA] probes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56966—Animal cells
- G01N33/56977—HLA or MHC typing
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6878—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids in eptitope analysis
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
- G16B20/20—Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2570/00—Omics, e.g. proteomics, glycomics or lipidomics; Methods of analysis focusing on the entire complement of classes of biological molecules or subsets thereof, i.e. focusing on proteomes, glycomes or lipidomes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Physics & Mathematics (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Analytical Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Genetics & Genomics (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Urology & Nephrology (AREA)
- Biophysics (AREA)
- Pathology (AREA)
- Oncology (AREA)
- Biochemistry (AREA)
- Mycology (AREA)
- Wood Science & Technology (AREA)
- Theoretical Computer Science (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Medical Informatics (AREA)
- Evolutionary Biology (AREA)
- Bioinformatics & Computational Biology (AREA)
- Virology (AREA)
- Food Science & Technology (AREA)
- General Physics & Mathematics (AREA)
Abstract
本發明提供允許選擇根據各種標準過濾之腫瘤新抗原決定基的系統及方法。在特定預期態樣中,該過濾包括查明產生該新抗原決定基之突變位於癌症驅動子基因中的步驟。
Description
本發明之技術領域為對組學資料進行計算分析以預測治療選擇方案,其尤其係關於基於新抗原決定基之免疫療法中之靶抗原決定基的選擇。
先前技術描述包括可適用於理解本發明之資訊。其並非承認本文所提供之資訊中之任一者為先前技術或與當前所主張之發明有關,或具體地或隱含地參考之任何公開案為先前技術。 本文中之所有公開案及專利申請案均以引用之方式併入,其程度如同每一個別公開案或專利申請案係特定且單獨地經指示為以引用的方式併入。當併入之參考文獻中之術語之定義或用途與本文所提供之術語之定義不一致或相反時,本文所提供之該術語之定義適用且參考文獻中之該術語之定義不適用。 靶向特定癌症常見之某些抗原的癌症免疫療法在一些患者中已產生顯著反應。令人遺憾地,儘管相同抗原之表現明顯,但許多患者未能對此類免疫療法作出反應。此失敗之一種可能原因可為免疫系統之各種效應細胞可能未以充足量存在,或可能已經耗竭。此外,患者中之細胞內抗原處理及HLA變異性可能導致抗原及/或抗原顯示之處理不足,從而導致治療上無效或缺乏反應。 為增加用於免疫療法之靶向物的選擇,近年來已考慮到隨機突變,此係由於腫瘤細胞中之一些隨機突變可產生獨特的腫瘤特異性抗原(新抗原決定基)。因此,且至少在概念上,新抗原決定基可為免疫療法提供獨特的精確靶向物。此外,已顯示極少量之肽可觸發溶胞性T細胞反應(例如,Sykulev等人,Immunity,第4卷,第6期,第565-571頁,1996年6月1日)。此外,由於許多癌症中之突變的數目相對較大,因此可能的靶向物之數目相對較高。鑒於此等發現,識別癌症新抗原決定基作為治療性靶向物已受到許多關注。令人遺憾地,當前資料似乎表明,所有或幾乎所有癌症新抗原決定基對患者及特定腫瘤為獨特的,且因此不能提供關於何種新抗原決定基可適用於治療上有效的免疫治療劑之任何特定指示。 為克服與用於免疫療法之較大數目可能靶向物相關的問題中之至少一些,可針對突變類型(例如,以確定錯義或無義突變)、轉錄水準過濾新抗原決定基以確認突變基因之轉錄且確認蛋白質表現。此外,可針對與患者之HLA系統的特異性結合進一步分析經如此過濾之新抗原決定基,如WO 2016/172722中所描述。雖然此系統有利地減少相對較大數目之潛在新抗原決定基,但此等新抗原決定基相對於治療結果之意義仍不確定。 因此,儘管識別新抗原決定基之多種方法為此項技術中已知的,但其所有或幾乎所有仍有一或多個不足之處。因此,將希望具有用於增加免疫療法中之治療反應之可能性的新抗原決定基識別之經改良系統及方法。
本發明主題係針對用於選擇用於免疫療法之新抗原決定基的各種組合物及方法,該免疫療法靶向不僅在腫瘤細胞上表現及呈現而且亦賦予該腫瘤細胞功能優勢之新抗原決定基。最佳地,所涵蓋新抗原決定基將包括癌症驅動子突變。因此,所涵蓋組合物及方法將使腫瘤細胞及其突變驅動子經受體液及細胞免疫反應且因此增加治療作用之可能性。 在本發明主題之一個態樣中,本發明人預期一種選擇用於癌症之免疫療法之新抗原決定基的方法,該方法包括自患者獲得來自腫瘤組織及匹配正常組織之組學資料,且使用該組學資料以判定複數個基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基的步驟。在另一步驟中,根據患者之HLA類型過濾基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基,從而獲得HLA匹配之新抗原決定基,且在又一步驟中,根據HLA匹配之新抗原決定基所影響之基因類型來過濾HLA匹配之新抗原決定基,從而獲得癌症驅動子新抗原決定基。 在此類方法中,進一步預期該組學資料包含選自由以下組成之群的至少兩種組學資料:全基因組定序資料、全外顯子組定序資料、RNAseq資料及定量蛋白質組資料,及/或判定該等複數個基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基之步驟包含來自腫瘤組織及匹配正常組織之組學資料的定位引導同步比對。在需要時,所預期方法可進一步包含根據選自由以下組成之群的先驗已知分子變異中之至少一者過濾該等基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基的步驟:單核苷酸多形現象、短缺失及插入多形現象、微衛星標記、短串聯重複、異型接合序列、多核苷酸多形現象及指定變異體。最典型地,腫瘤組織為實體腫瘤組織且匹配正常組織為血液。 有利地,根據HLA類型過濾患者特異性及腫瘤特異性新抗原決定基的步驟可使用複數個不同個別新抗原決定基序列針對該等新抗原決定基中之每一者進行,其中經改變胺基酸在新抗原決定基序列內具有不同位置。舉例而言,個別新抗原決定基序列可具有7個與20個胺基酸之間的長度。 進一步預期根據HLA類型過濾之步驟可包括根據患者組學資料判定HLA類型。通常但未必,根據HLA類型過濾之步驟進行至至少2位數之深度,且更典型地至少4位數。另外或替代地,根據HLA類型過濾之步驟亦可包含測定新抗原決定基與患者之至少一種MHC I類子型及至少一種MHC II類子型的親和力。舉例而言,HLA匹配之新抗原決定基與患者之至少一種MHC I類子型或至少一種MHC II類子型的親和力可等於或小於150 nM。 對於受影響之基因類型,通常預期該基因類型為癌症驅動子及/或乘客基因,通常為選自由以下組成之群的癌症之基因:ALL、AML、BLCA、BRCA、CLL、CM、COREAD、ESCA、GBM、HC、HNSC、LUAD、LUSC、MB、NB、NSCLC、OV、PRAD、RCCC、SCLC、STAD、THCA及UCEC。舉例而言,合適之癌症驅動子基因列於表1中。 在需要時,合適之方法可進一步包含判定受影響癌症驅動子基因中之功能失常的步驟。在此情況下,可產生對靶向由受影響癌症驅動子基因編碼之蛋白質的非免疫治療藥物的建議。此外,亦預期本文所提供之方法可進一步包括使用癌症驅動子新抗原決定基來製備免疫治療劑之步驟。舉例而言,合適之免疫治療劑可包含以下中之至少一者:與癌症驅動子新抗原決定基具有結合特異性之合成性抗體、合成性癌症驅動子新抗原決定基、編碼癌症驅動子新抗原決定基之核酸、攜載與癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體的免疫勝任細胞,及包含編碼癌症驅動子新抗原決定基之核酸的重組病毒。 因此,本發明人亦預期使用免疫療法治療患者之癌症的方法。此類方法將包括自患者獲得來自腫瘤組織及匹配正常組織之組學資料,且使用該組學資料以判定複數個基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基的步驟。在另一步驟中,癌症驅動子新抗原決定基衍生自基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基。在又一步驟中,向患者投與包含以下中之至少一者的免疫治療劑:與癌症驅動子新抗原決定基具有結合特異性之合成性抗體、合成性癌症驅動子新抗原決定基、編碼癌症驅動子新抗原決定基之核酸、攜載與癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體的免疫勝任細胞,及包含編碼癌症驅動子新抗原決定基之核酸的重組病毒。 如前所述,預期組學資料將通常包含選自由以下組成之群的至少兩種組學資料:全基因組定序資料、全外顯子組定序資料、RNAseq資料及定量蛋白質組資料,及/或判定該等複數個基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基之步驟可包含來自腫瘤組織及匹配正常組織之組學資料的定位引導同步比對。所預期方法亦可包括根據選自由以下組成之群的先驗已知分子變異中之至少一者來過濾基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基的另一步驟:單核苷酸多形現象、短缺失及插入多形現象、微衛星標記、短串聯重複、異型接合序列、多核苷酸多形現象及指定變異體。 通常但未必,衍生癌症驅動子新抗原決定基之步驟將包括根據患者之HLA類型來過濾患者特異性及腫瘤特異性新抗原決定基的步驟(其可使用其中經改變胺基酸在新抗原決定基序列內具有不同位置之複數個不同個別新抗原決定基序列,其中該等個別新抗原決定基序列可具有7個與20個胺基酸之間的長度)。此外,根據HLA類型過濾之步驟可包含根據患者組學資料判定HLA類型,及/或可進行至至少4位數之深度,及/或可包含測定新抗原決定基與患者之至少一種MHC I類子型及至少一種MHC II類子型的親和力。 所預期癌症驅動子新抗原決定基可位於選自由以下組成之群的基因中:ALL、AML、BLCA、BRCA、CLL、CM、COREAD、ESCA、GBM、HC、HNSC、LUAD、LUSC、MB、NB、NSCLC、OV、PRAD、RCCC、SCLC、STAD、THCA及UCEC,且例示性癌症驅動子基因列於表1中。此外,所預期方法可包括投與靶向包含癌症驅動子新抗原決定基之蛋白質之非免疫治療藥物的步驟。 因此,本發明人亦預期一種包含偶合至以下各者之載劑的免疫治療組合物:(i)與患者特異性癌症驅動子新抗原決定基具有結合特異性之合成性抗體,(ii)合成性患者特異性癌症驅動子新抗原決定基,(iii)編碼患者特異性癌症驅動子新抗原決定基之核酸,或(iv)與患者特異性癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體。 合適之載劑可包括單一蛋白質或可包含醫藥學上可接受之聚合物。替代地,載劑亦可為免疫勝任細胞(例如,CD8+ T細胞或NK細胞)或重組病毒。按需要,可包括適合於注射或輸注之醫藥學上可接受之載劑。 因此,且自不同視角觀察,本發明人亦預期免疫治療劑在治療癌症中之用途,其中該免疫治療劑包含以下中之至少一者:與患者特異性癌症驅動子新抗原決定基具有結合特異性之合成性抗體、合成性患者特異性癌症驅動子新抗原決定基、編碼患者特異性癌症驅動子新抗原決定基之核酸、攜載與患者特異性癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體的免疫勝任細胞,及包含編碼患者特異性癌症驅動子新抗原決定基之核酸的重組病毒。 舉例而言,合成性抗體可偶合至NK細胞或偶合至包含單一蛋白質或包含醫藥學上可接受之聚合物的載劑,及/或患者特異性合成性癌症驅動子新抗原決定基可偶合至包含單一蛋白質或包含醫藥學上可接受之聚合物的載劑。替代地,編碼患者特異性癌症驅動子新抗原決定基之核酸可包含於免疫勝任細胞或病毒中,或偶合至包含單一蛋白質或包含醫藥學上可接受之聚合物的載劑。 因此,本發明人亦預期一種重組免疫勝任細胞(例如,CD8+ T細胞或NK細胞,或NK92衍生物),其包含編碼與患者特異性癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體,或編碼患者特異性癌症驅動子新抗原決定基之核酸。 本發明主題之各種目標、特徵、態樣及優勢將自以下較佳實施例之詳細描述以及隨附圖式變得更顯而易見,在該等隨附圖式中相同編號表示相同組分。
本申請案主張2016年2月12日申請之具有序列號62/294665之美國臨時申請案之優先權,且該申請案以引用之方式併入本文中。 本發明人現已發現,基於新抗原決定基之免疫療法可進一步藉由靶向賦予腫瘤細胞功能優勢之所表現患者特異性及腫瘤特異性新抗原決定基來加以改良。最佳地,新抗原決定基將位於由已知、預測或懷疑之癌症驅動子基因編碼的蛋白質中。因此,預期對此癌症驅動子新抗原決定基之免疫反應將不僅產生細胞毒性免疫反應,而且亦產生針對癌症驅動子蛋白質之體液反應。舉例而言,當癌症驅動子基因為KIT (肥大細胞/幹細胞生長因子受體)且包括新抗原決定基時,與KIT新抗原決定基結合之抗體可不僅藉由NK細胞及T細胞標記用於細胞毒性破壞之蛋白質,而且亦可抑制經由受體路徑之信號傳導且由此抑制癌症驅動子功能。 為此,預期可在較佳地使用患者腫瘤物質(例如,活檢樣品)及匹配之正常組織(非腫瘤,通常為同一患者之健康組織)的方法中識別癌症驅動子新抗原決定基。接著可對患者樣品執行組學分析以獲得組學資料,最典型地基因組學資料(諸如全基因組序列資料、全外顯子組資料等)、轉錄組學資料(且尤其RNAseq資料)及/或蛋白質組學資料(其可為定性的或定量的)。接著可使用組學資料來識別且過濾(經表現且HLA匹配之患者特異性及腫瘤特異性)癌症驅動子新抗原決定基,如下文更詳細地所描述。經如此識別之癌症驅動子新抗原決定基接著可用於使用各種治療模式之免疫療法中,該等治療模式包括基於細胞之治療、癌症疫苗、治療性抗體等。 新抗原決定基可表徵為產生獨特且腫瘤特異性抗原之腫瘤細胞中之所表現隨機突變。因此,自不同視角觀察,新抗原決定基可藉由考慮突變之類型(例如,缺失、插入、顛換、轉換、易位)及影響(例如,無義、錯義、框移等)來加以識別,此可由此充當消除沉默突變及其他不相關(例如,未表現)突變之第一內容過濾。應進一步瞭解,新抗原決定基序列可定義為具有相對較短長度之序列延伸段(例如,7至11個聚體),其中此延伸段將包括胺基酸序列之改變。最典型地,經改變胺基酸將處於中心胺基酸位置處或附近。舉例而言,典型新抗原決定基可具有以下結構:A4
-N-A4
或A3
-N-A5
或A2
-N-A7
或A5
-N-A3
或A7
-N-A2
,其中A為蛋白型胺基酸且N為經改變胺基酸(相對於野生型胺基酸或相對於匹配的正常胺基酸)。舉例而言,如本文中涵蓋之新抗原決定基序列包括具有相對較短長度之序列延伸段(例如,5至30個聚體,更典型地7至11個聚體,或12至25個聚體),其中此延伸段包括胺基酸序列之改變。 因此,應瞭解,根據經改變胺基酸之位置,單一胺基酸改變可呈現於包括經改變胺基酸之大量新抗原決定基序列中。有利地,此序列變異性允許新抗原決定基之多個選擇且因此增加潛在有用靶向物之數目,接著可基於一或多個所需性狀(例如,與患者HLA類型之最高親和力、最高結構穩定性等)來選擇該等靶向物。最典型地,新抗原決定基將經計算具有2至50個胺基酸之間的長度,更典型地具有5至30個胺基酸之間的長度,且最典型地具有9至15個胺基酸之間的長度,其中經改變胺基酸較佳地居中定位或另外以提高其與MHC之結合的方式定位。舉例而言,在抗原決定基由MHC-I錯合物表示時,典型的新抗原決定基長度將為約8至11個胺基酸,而經由MHC-II錯合物表示之典型的新抗原決定基長度將具有約13至17個胺基酸之長度。如將容易瞭解,由於經改變胺基酸在新抗原決定基中之位置可不為中心,因此實際肽序列及新抗原決定基之實際拓樸可顯著變化。 當然,應瞭解,新抗原決定基之識別或發現可以各種生物材料開始,包括新鮮活檢體、冷凍或以其他方式保存之組織或細胞樣品、循環腫瘤細胞、外來體、各種體液(且尤其血液)等。因此,組學分析之合適方法包括核酸定序、(且特定言之對DNA執行之NGS方法(例如,伊路米那定序(Illumina sequencing)、離子流定序(ion torrent sequencing)、454焦磷酸定序、奈米孔定序等))、RNA定序(例如,RNAseq、基於反轉錄之定序等)及蛋白質定序或基於質譜之定序(例如,SRM、MRM、CRM等)。 因此,且尤其對於基於核酸之定序,應特別認識到,腫瘤組織之高通量基因組定序將允許快速識別新抗原決定基。然而,必須瞭解,當如此獲得之序列資訊與標準參考物相比較時,正常發生之患者間變異(例如,由於SNP、較短插入缺失、不同數目之重複序列等)以及異型接合性將產生相對較大數目之潛在偽陽性新抗原決定基。應注意,在將患者之腫瘤樣品與同一患者之匹配正常(亦即,非腫瘤)樣品相比較時可消除此不準確性。 在本發明主題之一個尤其較佳態樣中,藉由腫瘤及匹配正常樣品兩者之全基因組定序及/或外顯子組定序(典型地以至少10倍之覆蓋深度,更典型地至少20倍)來進行DNA分析。替代地,DNA資料亦可由來自先前序列測定之已建立序列記錄(例如,SAM、BAM、FASTA、FASTQ或VCF檔案)提供。因此,資料集可包括未處理或處理之資料集,且例示性資料集包括具有BAMBAM格式、SAMBAM格式、FASTQ格式或FASTA格式之彼等資料集。然而,尤其較佳地,該等資料集以BAMBAM格式提供或作為BAMBAM diff對象提供(參見例如US2012/0059670A1及US2012/0066001A1)。此外,應注意,該等資料集反映同一患者之腫瘤及匹配正常樣品,以如此獲得患者特異性及腫瘤特異性資訊。因此,可排除不引起腫瘤(例如,沉默突變、SNP等)之遺傳生殖細胞系改變。當然,應認識到,腫瘤樣品可來自原始腫瘤、來自開始治療後之腫瘤、來自復發性腫瘤或轉移性位點等。在多數情況下,患者之匹配正常樣品可為血液,或來自與腫瘤相同之組織類型的非患病組織。 同樣地,對序列資料之計算分析可以多種方式進行。然而,在最佳方法中,使用BAM檔案及BAM伺服器藉由如(例如) US 2012/0059670A1及US 2012/0066001A1中所揭示之腫瘤及正常樣品之定位引導同步比對來計算機(in silico)執行分析。此分析有利地減少偽陽性新抗原決定基且顯著地減少對記憶體及計算資源的需求。 應注意,應讀取針對電腦之任一語言以包括計算器件之任何合適組合,包括伺服器、介面、系統、資料庫、代理程式、對等機、引擎、控制器,或單獨地或集成操作之其他類型計算器件。吾人應瞭解該等計算器件包含經組態以執行儲存於有形、非暫時性電腦可讀儲存媒體(例如,硬碟機、固態磁碟機、RAM、快閃記憶體、ROM等)上之軟體指令的處理器。該等軟體指令較佳地組態計算器件以提供如下文關於本發明設備所論述之作用、責任或其他功能。另外,所揭示技術可利用包括儲存軟體指令之非暫時性電腦可讀媒體的電腦程式產品實行,該等軟體指令讓處理器執行與基於電腦之演算法、程序、方法或其他指令之實施相關聯的所揭示步驟。在尤其較佳的實施例中,各種伺服器、系統、資料庫或介面可能基於HTTP、HTTPS、AES、公鑰-私鑰交換、網路服務API、已知財務交易協定或其他電子資訊交換方法使用標準化協定或演算法來交換資料。器件間之資料交換可在封包交換式網路(網際網路、LAN、WAN、VPN或其他類型之封包交換式網路)、電路交換式網路、小區交換式網路或其他類型之網路上進行。 自不同視角觀察,可確立具有5個至25個胺基酸之間的預定長度且包括至少一個經改變胺基酸之序列的患者特異性及癌症特異性電腦模擬集合。此集合通常針對每一個經改變胺基酸,包括其中經改變胺基酸之位置不相同的至少兩個、至少三個、至少四個、至少五個或至少六個成員。此集合接著可用於其他過濾(例如,根據子細胞位置、轉錄/表現水準、MHC-I及/或II親和力等),如下文更詳細地所描述。 舉例而言,且使用對腫瘤及匹配正常序列資料之同步定位引導分析,本發明人預先自各種癌症及患者識別各種癌症新抗原決定基,包括以下癌症類型:BLCA、BRCA、CESC、COAD、DLBC、GBM、HNSC、KICH、KIRC、KIRP、LAML、LGG、LIHC、LUAD、LUSC、OV、PRAD、READ、SARC、SKCM、STAD、THCA及UCEC。所有新抗原決定基資料可見於以引用之方式併入本文中之國際申請案PCT/US16/29244中。 根據癌症之類型及階段,應注意,並非所有經識別新抗原決定基將必定在向患者提供檢查點抑制劑時在患者中產生治療上同樣有效之反應。實際上,在此項技術中熟知,僅部分新抗原決定基將產生免疫反應。為增加治療上所需反應之可能性,可進一步過濾新抗原決定基。當然,應瞭解,後階段分析不必考慮沉默突變以用於本文所呈現方法之目的。然而,除突變類型(例如,缺失、插入、顛換、轉換、易位)以外,較佳突變分析將亦提供突變之影響(例如,無義、錯義等)的資訊,且可由此充當消除沉默突變之第一內容過濾。舉例而言,在突變為框移、無義及/或錯義突變之情況下,可針對其他考慮因素選擇新抗原決定基。 在其他過濾方法中,新抗原決定基亦可經受子細胞定位參數之具體分析。舉例而言,若規定新抗原決定基識別為具有細胞膜相關位置(例如,位於細胞之細胞膜之外部)及/或若計算機結構性計算值確定新抗原決定基可能為暴露之溶劑,或呈現結構上穩定之抗原決定基(例如,J Exp Med
2014)等,則可選擇新抗原決定基序列用於其他考慮因素。 對於過濾新抗原決定基,大體上考慮在組學(或其他)分析揭露新抗原決定基實際上經表現之情況下,新抗原決定基尤其適於在本文中使用。新抗原決定基之表現識別及表現水準可以此項技術中已知之全部方式進行且較佳之方法包括定量RNA(hnRNA或mRNA)分析及/或定量蛋白質組學分析。最通常地,新抗原決定基包括之臨限值位準將為相應匹配正常序列之表現水準之至少20%、至少30%、至少40%,或至少50%的表現水準,因此確保(新)抗原決定基至少對免疫系統潛在『可見』。因此,大體上較佳的係組學分析亦包括對基因表現之分析(轉錄組學分析)以有助於識別具有突變之基因的表現量。 存在此項技術中已知之轉錄組學分析的多個方法,且認為所有已知方法適於在本文中使用。舉例而言,較佳之材料包括mRNA及初級轉錄物(hnRNA),且RNA序列資訊可自反轉錄之polyA+
-RNA獲得,其依次自相同患者之腫瘤樣品及匹配正常(健康)樣品獲得。同樣地,應注意雖然polyA+
-RNA通常較佳為轉錄組之表示,但其他形式之RNA (hn-RNA、非聚腺苷酸化之RNA、siRNA、miRNA等)亦被認為適於在本文中使用。較佳之方法包括定量RNA (hnRNA或mRNA)分析及/或尤其包括RNAseq之定量蛋白質組學分析。在其他態樣中,使用基於RNA-seq、qPCR及/或rtPCR之方法進行RNA定量及定序分析,但認為各種替代性方法(例如,基於固相雜化之方法)亦適用。自另一視角觀察,轉錄組學分析可適用以識別且定量具有癌症特異性及患者特異性突變之基因。 類似地,可以多個方式進行蛋白質組學分析以確定新抗原決定基之RNA之實際轉譯,且蛋白質組學分析之所有已知方式涵蓋於本文中。然而,尤佳之蛋白質組學方法包括基於抗體之方法及質譜方法。此外,應注意蛋白質組學分析可不僅提供關於蛋白質本身之質量或定量資訊,在蛋白質具有催化或其他功能活性之情況下亦可包括蛋白質活性資料。用於傳導蛋白質組學分析之一個例示性技術描述於US 7473532中,其以引用之方式併入本文中。蛋白質表現之識別及甚至定量化之其他合適方法包括各種質譜分析(例如選擇性反應監測(SRM)、多反應監測(MRM),及連續反應監測(CRM))。因此,應瞭解以上方法將提供患者及腫瘤特異性新抗原決定基,其可藉由蛋白質之子細胞定位來進一步過濾,該蛋白質含有新抗原決定基(例如,細胞膜位置)、表現強度(例如,相比於相同患者之匹配正常過度表現)等。 在過濾之又一態樣中,新抗原決定基可對照比較含有已知(例如,患者或一批患者之)人類序列之資料庫以避免使用人類相同序列。此外,在SNP存在於腫瘤及匹配正常序列兩者中之情況下,過濾亦可包括由於患者中之SNP而移除新抗原決定基序列。舉例而言,dbSNP (單核苷酸多形現象資料庫)為美國國家生物技術信息中心(National Center for Biotechnology Information;NCBI)與國家人類基因組研究院(National Human Genome Research Institute;NHGRI)合作研發且代管之不同物種內遺傳性差異的免費公共存檔。儘管資料庫之名稱意指僅一類多形現象(單核苷酸多形現象(SNP))之集合,但其實際上含有相對廣泛範圍之分子變異:(1)SNP、(2)短缺失及插入多形現象(插入缺失/DIP)、(3)微衛星標記或短串聯重複(STR)、(4)多核苷酸多形現象(MNP)、(5)異型接合序列及(6)指定變異體。dbSNP接受表觀中性多形現象、對應於已知表現型之多形現象及無變異區域。使用此資料庫及如上文所描述之其他過濾選擇方案,可過濾患者及腫瘤特異性新抗原決定基以移除彼等已知序列,產生具有基本上經減少之偽陽性的複數個新抗原決定基序列之序列集。 然而,即使過濾,應認識到並非所有新抗原決定基將對免疫系統可見,此係因為新抗原決定基亦需要在患者之MHC錯合物上表現。實際上,僅一部分新抗原決定基將具有表現之充足親和力,且較大分集之MHC錯合物將排除使用大部分(若並非所有)常見新抗原決定基。因此,在免疫療法之上下文中,應由此顯而易見的係在新抗原決定基結合至MHC錯合物且由該錯合物表現之情況下,新抗原決定基將更可能有效。自另一視角觀察,使用檢查點抑制劑之治療成效需要經由MHC錯合物表現之多個新抗原決定基,其中該新抗原決定基必須具有與患者之HLA類型的最小親和力。因此,應瞭解有效結合及表現為患者之新抗原決定基之序列與特定HLA類型之組合功能。最通常地,HLA類型測定包括至少三個MHC-I子型(例如,HLA-A、HLA-B、HLA-C)及至少三個MHC-II子型(例如,HLA-DP、HLA-DQ、HLA-DR),較佳地各子型測定至至少2位數深度或至少4位數深度。然而,本文亦涵蓋較大深度(例如,6位數、8位數)。 一旦查明患者之HLA類型(使用已知化學或計算機測定),用於HLA類型之結構溶液經計算或自資料庫獲得,接著將其用於計算機對接模型以測定(通常經過濾之)新抗原決定基與HLA結構溶液之結合親和力。如下文將進一步論述,用於測定結合親和力之合適系統包括NetMHC平台(參見(例如) Nucleic Acids Res. 2008年7月1日; 36(網頁伺服器問題): W509-W512.)。接著選擇對於先前測定之HLA類型具有高親和力(例如,小於100 nM、小於75 nM、小於50 nM)之新抗原決定基用於療法創建,以及瞭解MHC-I/II子型。 可使用此項技術中熟知之濕化學中之各種方法進行HLA測定,且認為所有此等方法適於在本文中使用。然而,在尤佳方法中,亦可使用含有在下文中更詳細地展示之大部分或全部已知及/或常見HLA類型之參考序列自組學資料計算機預測HLA類型。 舉例而言,在根據本發明性主題之一個較佳方法中,由資料庫或定序分析裝置提供映射至染色體6p21.3 (或接近/在發現HLA對偶基因之任何其他位置)之相對較大數目之患者序列讀段。最通常地,該等序列讀段將具有約100至300個鹼基之長度且包含後設資料,該後設資料包括讀段質量、校準資訊、定向、位置等。舉例而言,合適之格式包括SAM、BAM、FASTA、GAR等。雖然不限於本發明主題,但通常較佳的係患者序列讀數提供至少5倍,更典型地至少10倍,甚至更典型地至少20倍,且最典型地至少30倍之覆蓋深度。 除患者序列讀數以外,所預期方法進一步採用包括已知及不同HLA對偶基因之複數個序列的一或多個參考序列。舉例而言,典型參考序列可為合成性(在無相應人類或其他哺乳動物對應體之情況下)序列,該序列包括具有該HLA類型之多個HLA對偶基因之至少一個HLA類型的序列節段。舉例而言,合適之參考序列包括HLA-A之至少50個不同對偶基因之已知基因組序列的集合。替代地或另外,參考序列亦可包括HLA-A之至少50個不同對偶基因之已知RNA序列的集合。當然,且如下文更詳細地進一步論述,參考序列不限於HLA-A之50個對偶基因,但可具有相對於HLA類型之替代性組合物及對偶基因之編號/組合物。最典型地,參考序列將呈電腦可讀格式且將由資料庫或其他資料儲存裝置提供。舉例而言,合適之參考序列格式包括FASTA、FASTQ、EMBL、GCG或GenBank格式,且可直接自公共資料儲存庫(例如,IMGT,國際免疫遺傳學資訊系統,或對偶基因頻率網路資料庫、EUROSTAM、URL:www.allelefrequencies.net)之資料獲得或建構。替代地,參考序列亦可自基於一或多個預定標準(諸如對偶基因頻率、種族對偶基因分佈、常見或罕見對偶基因類型等)之個別已知HLA對偶基因建構。 使用參考序列,患者序列讀段現可穿過de Bruijn曲線圖以識別具有最好擬合之對偶基因。在此上下文中,應注意每一個體攜載每一HLA類型之兩個對偶基因,且此等對偶基因可為非常類似的,或在一些情況下甚至為相同的。此類似性高度造成傳統校準方案之顯著問題。本發明人現已發現可使用一種方法解析HLA對偶基因及甚至非常接近相關之對偶基因,在該方法中,藉由將序列讀數分解成相對較小之k個聚體(通常地具有10至20個鹼基之間的長度),且藉由實施加權表決方法建構de Bruijn曲線圖,在該加權投票方法中,各患者序列讀數提供對匹配對偶基因之序列的序列讀數之k個聚體的對偶基因中之每一者的投票(「定量讀數支援」)。對偶基因之累積最高投票指示最可能預測之HLA對偶基因。此外,大體上較佳的係為對偶基因之匹配的各片段亦用以計算彼對偶基因之整個覆蓋度及覆蓋度之深度。 可按需要進一步改良或精細得分,尤其在許多高命中類似的情況下(例如,在其得分之重要部分來自高度共用之k個聚體集的情況下)。舉例而言,得分精確化可包括稱重流程,其中將基本上與當前高命中類似(例如,> 99%,或其他預定值)之對偶基因自未來考慮因素中移除。接著根據一個因數(例如,0.5)處重新加權當前高命中所使用之k個聚體之計數,且藉由求和此等加權之計數重新計算各HLA對偶基因之得分。重複此選擇方法以發現新的高命中。可甚至使用允許識別由腫瘤表現之對偶基因的RNA序列資料進一步改良方法之精確性,該對偶基因有時可僅為DNA中存在之2個對偶基因中的1個對偶基因。在預期之系統及方法之其他有益態樣中,DNA或RNA或DNA與RNA兩者之組合可經處理以做出高度精確的且可衍生自腫瘤或血液DNA或RNA之HLA預測。用於較高精確性計算機HLA分型之其他態樣、合適方法及考慮因素描述於國際PCT/US16/48768中,其以引用之方式併入本文中。 在識別患者及腫瘤特異性新抗原決定基及HLA類型後,可藉由是新抗原決定基對接至HLA且(例如)使用NetMHC測定最好黏合劑(例如,最低KD
,例如小於500 nM,或小於250 nM,或小於150 nM,或小於50 nM)來進行其他計算分析。應瞭解此方法將不僅識別對與患者及腫瘤為真正的特異性新抗原決定基,而且識別最可能在細胞上表現且由此最可能誘發具有治療性作用之免疫反應的彼等新抗原決定基。當然,亦應瞭解可活體外生物化學驗證因此識別之經HLA匹配之新抗原決定基,之後編碼抗原決定基之核酸作為淨負荷包括於如下文進一步論述之病毒中。 當然,應瞭解患者之HLA類型與患者特異性及癌症特異性新抗原決定基之匹配可使用除NetMHC以外之系統,及包括以下之合適系統來進行:NetMHC II、NetMHCpan、IEDB分析資源(URL immuneepitope.org)、RankPep、PREDEP、SVMHC、Epipredict、HLABinding,及其他(參見例如J Immunol Methods
2011;374:1-4)。在計算最高親和力中,應注意可使用其中經改變之胺基酸之位置經移動(同前文獻)的新抗原決定基序列之集合。替代地,或此外,可藉由添加N端及/或C端修飾來實施對新抗原決定基之修飾以進一步增加表現之新抗原決定基與患者之HLA類型的結合。因此,新抗原決定基可天然識別或進一步經修飾以更好匹配特定的HLA類型。此外,在需要之情況下,可計算相應野生型序列之結合(亦即,在無胺基酸改變之情況下的新抗原決定基序列)以確保高差異性親和力。舉例而言,新抗原決定基與其相應野生型序列之間的MHC結合之尤其較佳較高差異性親和力為至少2倍、至少5倍、至少10倍、至少100倍、至少500倍、至少1000倍等。 在實現新抗原決定基之過濾的所需水準(例如,藉由腫瘤相對於正常過濾之新抗原決定基,及/或表現水準,及/或子細胞位置,及/或患者特異性HLA匹配,及/或已知變異體)後,預期其他過濾步驟考慮受新抗原決定基影響之基因型。舉例而言,合適之基因類型包括癌症驅動子基因、與調節細胞分裂相關之基因、與細胞凋亡相關之基因,及與信號轉導相關之基因。然而,在尤其較佳態樣中,癌症驅動子基因為尤其較佳的(其可功能性涵括各種基因類型,包括受體基因、信號轉導基因、轉錄調節基因等)。在其他預期態樣中,合適之基因類型亦可為已知之乘客基因及涉及代謝之基因。 如之前已提及,預期認為靶向癌症驅動子基因可提供增強治療作用,因為對抗由癌症驅動子基因編碼之蛋白質的免疫反應將不僅提高對抗腫瘤細胞之基於細胞之細胞毒素作用,而且有助於功能性干擾由具有癌症驅動新抗原決定基之癌症驅動子基因編碼的蛋白質。自另一視角觀察,使用本文所涵蓋之系統及方法的治療反應將在免疫治療性方法及更傳統之基於蛋白質功能的方法兩者中靶向癌細胞。因此,預期由經過濾之新抗原決定基進一步分析,以測定其與特定基因之相關性(例如,經過濾之新抗原決定基存在於經轉錄基因之外顯子中或存在於mRNA中),且該基因接著經識別為屬於需要之基因型,且尤其為癌症驅動子基因。舉例而言,存在於癌症驅動子基因中之新抗原決定基經識別為癌症驅動新抗原決定基。 對於作為癌症驅動子基因之基因的識別或其他測定(例如,預測),各種方法及預測算法為此項技術中已知,且認為適於在本文中使用。舉例而言,合適之演算法包括MutsigCV (Nature
2014, 505(7484):495-501)、ActiveDriver (Mol Syst Biol
2013, 9:637)、MuSiC (Genome Res
2012, 22(8):1589-1598)、OncodriveClust (Bioinformatics
2013, 29(18):2238-2244)、OncodriveFM (Nucleic Acids Res
2012,40(21):e169)、OncodriveFML (Genome Biol
2016, 17(1):128)、腫瘤抑制因子及致癌基因(TUSON) (Cell
2013, 155(4):948-962), 20/20+ (https://github.com/KarchinLab/2020plus)及oncodriveROLE (Bioinformatics
(2014) 30 (17): i549-i555)。 亦可使用概率路徑分析工具識別癌症驅動子基因,且尤其較佳之工具包括PARADIGM (Bioinformatics
, 2010,第26卷 (第i237-i245頁))。PARADIGM藉由自觀測結果D之資料集汲取推斷來評估在遺傳性路徑簡圖ϕ之上下文中的基因之活性。路徑簡圖ϕ描述隱藏基因表現變量之間的相連性、其相應觀測資料及任何調節輸入及輸出。變量藉由編碼概率依賴性的彼此約束相連之變量因子彼此相連。PARADIGM接著對來源於ϕ之因子曲線圖使用置信傳播演算法以計算各基因、錯合物、蛋白質家族及藉由組合基因表現、複本數及遺傳性相互作用之細胞處理之推斷路徑程度(inferred pathway levels; IPL)。正值IPL反映基因在腫瘤中更可能為活性的程度(且因此可為癌症驅動子基因),且負值IPL反映基因在腫瘤中相對於在正常者更可能為非活性的程度。此類方法可藉由基於將觀測之基因活性之後階段結果與如其他處所描述之自其調節輸入預測之結果進行比較的直覺來計算偏移(PARADIGM-SHIFT)得分而進一步精細化(Bioinformatics
(2012) 28 (18): i640-i646)。 替代地或另外,亦可利用已知癌症驅動子基因之不同來源及其與特異性癌症之相關性識別癌症驅動子基因。舉例而言,驅動突變體之Intogen目錄(2016.5;URL: www.intogen.org)含有藉由癌症基因組解譯器在28個腫瘤類型之泛癌症群組之6,792個外顯子組中進行驅動子分析之結果。根據現代化臨床及實驗資料識別經證實之致癌突變,而藉由OncodriveMUT方法預測未知意義之突變的影響。類似地,Intogen癌症驅動子資料庫(2014.12;URL: www.intogen.org)含有關於經Rubio-Perez及Tamborero等人識別為驅動子之基因的資訊(Cancer Cell
27 (2015),第382-396頁)。 此外,下表 1
提供最常見癌症驅動子基因之例示性選擇及其在特定癌症中之作用。 表 1
用於特定癌症且適合於與本文所呈現之教示結合使用之其他例示性癌症驅動子基因包括以下各者: ALL (急性淋巴球性白血病)驅動子基因包括CNOT1、CNOT3、FBXW7、FLT3、KRAS、NF1、NRAS、PTEN、RB1、RPL5、SH2B3及TP53。 AML (急性骨髓白血病)驅動子基因包括ASXL1、BCOR、CBFB、CEBPA、CHD4、CUL1、DIS3、DNMT3A、EGFR、EZH2、FLT3、IDH1、IDH2、KDM6A、KIT、KRAS、MED12、NF1、NPM1、NRAS、PHF6、PRPF8、PTPN11、RAD21、RUNX1、STAG2、SUZ12、TET2、THRAP3、TP53、U2AF1及WT1。 BLCA (膀胱癌)驅動子基因包括ACSL6、ACTB、ACTG1、ADAM10、AFF4、AHNAK、AHR、ANK3、APC、AQR、ARFGAP1、ARFGEF2、ARHGAP26、ARHGAP35、ARID1A、ARID1B、ATR、BAP1、BCLAF1、BCOR、BLM、BMPR2、BRAF、BRCA1、CAD、CARM1、CASP8、CAST、CAT、CCAR1、CCT5、CDH1、CDK12、CDKN1A、CDKN1B、CDKN2A、CEP290、CHD3、CHD9、CHEK2、CIC、CLASP2、CLSPN、CLTC、CNOT1、COPS2、CSDE1、CTCF、CTNNB1、CUL2、DDX3X、DDX5、DICER1、DIS3、DLG1、EEF1B2、EIF2AK3、EIF4A2、EIF4G1、ELF1、ELF3、EP300、ERBB2IP、ERBB3、ERCC2、FAM123B、FAT1、FBXW7、FGFR2、FGFR3、FKBP5、FLT3、FN1、FUS、G3BP2、GNAS、GOLGA5、GPS2、HLA-A、HNRPDL、HRAS、HSP90AA1、HSP90AB1、HSPA8、IDH1、IREB2、IRS2、KDM6A、KEAP1、KLF6、LIMA1、MAP3K1、MAP3K4、MAP4K3、MECOM、MED12、MED24、MET、MGA、MLH1、MLL2、MLL3、MTOR、MYH10、MYH11、NAP1L1、NCF2、NCOR2、NDRG1、NFE2L2、NOTCH1、NRAS、NUP107、NUP98、PCDH18、PCSK6、PHF6、PIK3CB、PIP5K1A、PTEN、PTPRU、RAD21、RASA1、RB1、RBM5、RHOA、RPSAP58、SETD2、SETDB1、SF3A3、SF3B1、SFPQ、SMAD4、SMC1A、SOS1、SOS2、STAG1、STAG2、STK4、SUZ12、TAF1、TAOK1、TAOK2、TBL1XR1、TBX3、TGFBR2、THRAP3、TNPO1、TP53、TP53BP1、TRIO、TSC1、TXNIP、ZFP36L2、ZMYM2及ZNF814。 BRCA (乳癌)驅動子基因包括ACO1、ACSL6、ACTB、ACVR1B、AFF4、AHNAK、AKAP9、AKT1、ANK3、APC、AQR、ARFGEF2、ARHGAP35、ARID1A、ARID2、ARID4B、ARNTL、ASH1L、ASPM、ATF1、ATIC、ATM、ATR、BAP1、BCOR、BMPR2、BNC2、BPTF、BRAF、BRCA1、BRCA2、CAD、CARM1、CASP8、CAST、CBFB、CCAR1、CCT5、CDH1、CDK12、CDKN1B、CEP290、CHD4、CHD9、CHEK2、CIC、CLASP2、CLSPN、CLTC、CNOT3、CSDE1、CSNK1G3、CTCF、CUL1、DDX3X、DDX5、DHX15、DIS3、EGFR、EIF1AX、EIF2C3、EIF4A2、EIF4G1、ELF1、EP300、ERBB2、ERBB2IP、ERCC2、FBXW7、FLT3、FMR1、FN1、FOXA1、FOXP1、FUBP1、FUS、G3BP2、GATA3、GOLGA5、GPS2、HCFC1、HLA-A、HLF、HNRPDL、HSPA8、IDH1、ITSN1、KALRN、KDM5C、KEAP1、KLF4、KRAS、LCP1、LPHN2、LRP6、MACF1、MAP2K4、MAP3K1、MAX、MECOM、MED12、MED23、MED24、MGA、MKL1、MLH1、MLL、MLL2、MLL3、MLLT4、MSR1、MTOR、MUC20、MYB、MYH11、MYH14、MYH9、NCOR1、NDRG1、NF1、NF2、NOTCH1、NOTCH2、NR4A2、NRAS、NSD1、NUP107、NUP98、PAX5、PBRM1、PCDH18、PCSK6、PHF6、PIK3CA、PIK3CB、PIK3R1、PIK3R3、PIP5K1A、POLR2B、PRKAR1A、PRKCZ、PTEN、PTGS1、PTPRU、RB1、RBBP7、RBM5、RFC4、RHEB、RPGR、RPL5、RUNX1、SEC24D、SETD2、SETDB1、SF3B1、SFPQ、SMAD4、SMARCA4、SOS1、SOS2、SPTAN1、SRGAP1、STAG1、STAG2、STIP1、STK11、STK4、SUZ12、SVEP1、TAF1、TBL1XR1、TBX3、TCF12、TCF7L2、TFDP1、TGFBR2、THRAP3、TNPO1、TOM1、TP53、TRIO、ZFP36L1及ZFP36L2。 CLL (慢性淋巴球性白血病)驅動子基因包括ACTG1、ANK3、ARID1A、ATM、BCOR、CLSPN、CNOT3、CREBBP、DDX3X、EGFR、EP300、ERBB2IP、FBXW7、FGFR2、FGFR3、HNRPDL、IDH1、IRF2、KDM6A、KRAS、MED12、MLL、MLL2、MLL3、MTOR、MYD88、NCOR1、NF1、NOTCH1、NRAS、PBRM1、PLCB1、RB1、SETDB1、SF3B1、STAG2、TP53及XPO1。 CM (皮膚黑素瘤)驅動子基因包括ACO1、ACSL3、ACTG1、ACTG2、ACVR1B、ACVR2A、AFF4、AHCTF1、AHNAK、AHR、AKT1、ANK3、AQR、ARFGAP1、ARFGEF2、ARHGAP26、ARHGAP29、ARHGAP35、ARHGEF2、ARHGEF6、ARID1B、ARID2、ASPM、ATF1、ATIC、ATP6AP2、ATRX、B2M、BAP1、BAZ2B、BCLAF1、BLM、BMPR2、BNC2、BPTF、BRAF、BRCA1、BRWD1、C15orf55、CASP1、CASP8、CAST、CAT、CBFB、CCAR1、CCT5、CDC73、CDH1、CDK4、CDKN1A、CDKN2A、CEP290、CHD1L、CHD3、CHD6、CHD9、CHEK2、CIC、CLASP2、CLCC1、CLOCK、CLSPN、CLTC、CNOT3、COL1A1、COPS2、CRTC3、CSDA、CSNK1G3、CTCF、CTNNB1、CUL1、CUL2、CUL3、CYLD、CYTH4、DDX3X、DDX5、DHX15、DICER1、DIS3、DLG1、DNMT3A、EIF1AX、EIF2AK3、EIF4A2、EIF4G1、EIF4G3、ELF1、ELF3、EP300、ERBB2IP、ERBB3、EZH2、FAF1、FANCI、FAS、FBXW7、FCRL4、FGFR3、FMR1、FN1、FOXP1、FUBP1、FXR1、G3BP2、GATA3、GNG2、GOLGA5、HDAC3、HDAC9、HLA-A、HLA-B、HLF、HNRPDL、HRAS、HSPA8、IDH1、IDH2、IREB2、IRF7、ITGA9、ITSN1、JMY、KDM5C、KDM6A、KLF4、KLF6、KRAS、LCP1、LDHA、LNPEP、LRP6、LRPPRC、MAGI2、MAP2K1、MAP2K4、MAP3K1、MAP3K11、MAP3K4、MAP4K3、MAT2A、MCM3、MCM8、MECOM、MED17、MED24、MEN1、MFNG、MKL1、MLH1、MLL3、MSR1、NCF2、NCKAP1、NCOR1、NDRG1、NF1、NF2、NFATC4、NFE2L2、NOTCH1、NPM1、NR2F2、NR4A2、NRAS、NTN4、NUP107、NUP98、PAX5、PCDH18、PER1、PHF6、PIK3C2B、PIK3CA、PIK3CB、PIK3R1、PIK3R3、PIP5K1A、PLCB1、POLR2B、POM121、PPP2R1A、PPP2R5A、PPP2R5C、PPP6C、PRRX1、PSMA6、PTEN、PTGS1、RAC1、RAD21、RAD23B、RASA1、RASA2、RB1、RBBP7、RGS3、RHEB、RHOA、RHOT1、RPL22、RPL5、RTN4、RUNX1、SEC24D、SETDB1、SF3A3、SF3B1、SFPQ、SMAD2、SMAD4、SMC1A、SMURF2、SOS1、SOS2、SOX9、SPOP、STAG1、STAG2、STK11、SUZ12、SVEP1、SYK、SYNCRIP、TAOK1、TBX3、TCF12、TCF4、TFDP1、TFDP2、TGFBR2、TJP2、TNPO1、TP53、TRERF1、USP6、VHL、VIM、WASF3、WIPF1、WNK1、WT1、XRN1、YBX1、ZC3H11A、ZFP36L2、ZMYM2、ZNF638及ZNF814。 COREAD (結腸直腸腺癌)驅動子基因包括ACO1、ACSL6、ACVR1B、AKAP9、APC、ARID1A、ARNTL、ASPM、ATM、ATRX、AXIN2、BCOR、BMPR2、BPTF、BRAF、BRWD1、CAD、CASP8、CDC73、CDK12、CDKN1B、CEP290、CHD4、CHD9、CLSPN、CNOT1、CREBBP、CTCF、CTNNB1、CUL1、DIS3、DNMT3A、EGFR、ELF3、FAM123B、FBXW7 FN1、FOXP1、FXR1、GATA3、GNAS、GOLGA5、IDH2、ITSN1、KRAS、LPHN2、MAP2K1、MAP3K4、MECOM、MED12、MED24、MGA、MLL2、MSR1、MYH10、NF1、NR2F2、NR4A2、NRAS、NTN4、NUP107、NUP98、PCBP1、PIK3CA、PIK3R1、POLR2B、PPP2R1A、PTEN、PTGS1、PTPN11、PTPRU、RAD21、RBM10、RTN4、RUNX1、SF3B1、SMAD2、SMAD4、SMC1A、SOS2、SOX9、SRGAP3、STAG2、SYNCRIP、TAF1、TBX3、TCF12、TCF7L2、TGFBR2、TP53、TP53BP1、TRIO、WIPF1、WT1及ZC3H11A。 DLBC (瀰漫性大B細胞淋巴瘤)驅動子基因包括ACTB、AKAP9、ARID1A、CHD4、CREBBP、FBXO11、MLL2、MYC、SMARCA4及TP53。 ESCA (食道癌)驅動子基因包括ACO1、ACSL6、ACVR1B、ADAM10、AFF4、AHR、ARFGEF2、ARHGAP26、ARHGAP35、ARID1A、ARID2、ARNTL、ASPM、ATM、ATR、ATRX、BAP1、BCLAF1、BLM、BPTF、CAPN7、CDH1、CDKN1B、CDKN2A、CEP290、CHD4、CIC、CLTC、CNOT1、CNOT3、CREBBP、CSNK1G3、CTNNB1、CUL3、DDX5、DLG1、EEF1A1、EGFR、EIF2AK3、EIF4G1、ELF3、EP300、ERBB2IP、ERCC2、EZH2、FBXW7、FGFR2、FLT3、HGF、HLA-B、IREB2、IRS2、ITSN1、KALRN、KDM6A、LRP6、MACF1、MAP2K4、MAP3K4、MED12、MET、MGA、MLL2、MSR1、MTOR、NCKAP1、NFE2L2、NSD1、NUP107、NUP98、PAX5、PIK3CA、PTPRU、RAD21、RBM10、RHOA、RTN4、SETD2、SF3B1、SHMT1、SMAD4、SMARCA4、SMC1A、SOX9、SPTAN1、SRGAP3、SYNCRIP、TAF1、TAOK1、TAOK2、TBX3、TP53、TP53BP1、TRIO、WT1、ZC3H11A、ZFP36L2及ZNF814。 GBM (多形性膠質母細胞瘤)驅動子基因包括ACAD8、ADAM10、AKAP9、ANK3、AQR、ARFGEF2、ARHGAP35、ARHGEF6、ARID1A、ARID2、ATRX、BAP1、BPTF、BRAF、BRCA1、CAD、CARM1、CASP1、CHD8、CLOCK、CLTC、CNOT1、CSDE1、CUL1、DIS3、EGFR、EZH2、FAT1、FN1、HDAC9、HSP90AB1、IDH1、KALRN、KDM5C、KDM6A、KDR、KRAS、LRP6、MAP3K4、MAP4K3、MAX、MEN1、MET、MLL、NCF2、NCOR1、NEDD4L、NF1、NFATC4、NR2F2、NUP107、PAX5、PBRM1、PCDH18、PIK3CA、PIK3CB、PIK3R1、PRPF8、PTEN、PTPN11、RB1、RPL5、RPSAP58、SF3B1、SIN3A、SOS1、SOX9、SPTAN1、STAG2、TGFBR2、TJP1、TP53、TRIO、WT1及ZNF814。 HC (肝癌)驅動子基因包括ACVR2A、APC、ARHGAP35、ARID1A、ARID1B、ARID2、ASH1L、ATRX、BLM、BPTF、CEP290、CNOT1、CTNNB1、FLT3、IDH1、ITSN1、MACF1、MLL3、MYH10、NF1、NFATC4、NFE2L2、PBRM1、PIK3CA、PTEN、RTN4、SETDB1、SF3B1、TBL1XR1及TP53。 HNSC (頭部及頸部鱗狀細胞癌)驅動子基因包括ACAD8、ACTB、ACTG1、ACVR2A、ADAM10、AHR、AKT1、APAF1、APC、ARFGAP1、ARFGEF2、ARHGAP35、ARHGEF6、ARID1B、ARID2、ATIC、ATM、ATP6AP2、ATR、ATRX、B2M、BAP1、BAZ2B、BCL11A、BMPR2、BNC2、BPTF、BRAF、BRCA1、BRWD1、CAD、CARM1、CASP1、CASP8、CAT、CCAR1、CCT5、CDH1、CDK12、CDKN1B、CDKN2A、CEP290、CHD9、CIITA、CLASP2、CLSPN、CNOT4、COL1A1、CSNK2A1、CTCF、CTNNB1、CUL1、CUL3、CYLD、DDX3X、DICER1、DNMT3A、EEF1A1、EGFR、EIF2C3、ELF1、ELF4、EP300、EPHA2、EZH2、FAT1、FAT2、FBXW7、FGFR2、FLT3、FMR1、FN1、FOXP1、FUBP1、G3BP2、GNAS、GPSM2、HLA-A、HLA-B、HNRPDL、HRAS、HSPA8、IREB2、IRF6、IRS2、KALRN、KDM5C、KDM6A、KLF6、LAMA2、LPHN2、MACF1、MAP3K1、MAP4K3、MED17、MEF2C、MEN1、MGA、MGMT、MLL、MLL2、MSR1、MTOR、MUC20、MYH9、NCF2、NCKAP1、NCOR1、NEDD4L、NF1、NFATC4、NFE2L2、NOTCH1、NOTCH2、NR4A2、NSD1、NUP107、PABPC3、PAX5、PBRM1、PCDH18、PIK3CA、PIK3R1、PIK3R3、POLR2B、PPP2R1A、PPP2R5C、PRPF8、PRRX1、PSIP1、RAC1、RAD21、RASA1、RASGRP1、RHOA、RPL22、RPSAP58、RUNX1、SEC24D、SF3B1、SIN3A、SMAD2、SMARCA4、SMC1A、SOX9、SPOP、SPTAN1、STAG2、STIP1、TAOK1、TAOK2、TBL1XR1、TBX3、TCF12、TCF4、TFDP1、TFDP2、TGFBR2、THRAP3、TJP2、TP53、TRIO、TRIP10、U2AF1、WHSC1、ZC3H11A及ZNF750。 LGG (低級別膠質瘤)驅動子基因包括ACO1、ARFGEF2、ARHGAP26、ARHGEF6、ARID1A、ARID1B、ARID2、ATRX、CAD、CDK12、CHEK2、CIC、DDX3X、EEF1B2、EGFR、EIF1AX、FAM123B、FAT1、FUBP1、HGF、IDH1、IDH2、KAT6B、MAX、MECOM、MET、MLL、MLL2、MTOR、NCOR1、NEDD4L、NF1、NF2、NOTCH1、PIK3CA、PIK3R1、PTEN、PTPN11、RASA1、RB1、SETD2、SMARCA4、TAF1、TCF12、TJP1、TP53、TRIO、ZMYM2、ZNF292及ZNF814。 LUAD (肺腺癌)驅動子基因包括ACAD8、ACO1、ACTG1、ACTG2、ACVR1B、ACVR2A、ADAM10、AFF4、AKT1、ARFGAP1、ARHGAP26、ARID1A、ATIC、ATP6AP2、BAP1、BAZ2B、BLM、BMPR2、BRAF、BRWD1、CAPN7、CARM1、CASP8、CAT、CCAR1、CCT5、CDH1、CDK12、CDKN1B、CDKN2A、CHD1L、CHEK2、CIC、CLASP2、CLSPN、CNOT3、CNOT4、COL1A1、COPS2、CREBBP、CRNKL1、CSNK1G3、CTCF、CTNNB1、CUL2、CUL3、CYLD、DDX3X、DDX5、DHX15、DNMT3A、EEF1B2、EFTUD2、EGFR、EIF2AK3、EIF2C3、EIF4A2、EIF4G1、EP300、EPHA4、EPHB2、ERBB2IP、ERCC2、EZH2、FAT1、FBXW7、FGFR2、FMR1、FN1、FUBP1、FXR1、G3BP1、G3BP2、GNAI1、GNG2、GPSM2、HLA-A、HSP90AA1、HSP90AB1、HSPA8、IDH1、IREB2、IRS2、KDM6A、KDR、KEAP1、KLF6、KRAS、LCP1、LDHA、LPHN2、MAP2K1、MAP2K4、MAP3K1、MAP3K4、MAP4K1、MAP4K3、MAX、MED17、MED24、MEN1、MET、MGA、MKL1、MLH1、MLL、MLL3、MMP2、MSR1、MYB、MYH10、NCK1、NCKAP1、NEDD4L、NF1、NF2、NFE2L2、NPM1、NRAS、NTN4、NTRK2、NUP107、NUP98、PAX5、PBRM1、PCSK6、PHF6、PIK3R1、PIK3R3、PIP5K1A、POLR2B、PPP2R1A、PPP2R5A、PRPF8、PRRX1、PSMA6、PSMD11、PTEN、PTGS1、PTPN11、RAD23B、RASA1、RB1、RBM10、RBM5、RHEB、RTN4、SETD2、SETDB1、SF3B1、SFPQ、SHMT1、SIN3A、SMAD2、SMAD4、SMARCA4、SMC1A、SOX9、SPRR3、STAG1、STIP1、STK11、STK4、SVEP1、SYNCRIP、TAOK1、TAOK2、TBL1XR1、TCF12、TCF4、TCF7L2、TFDP1、TGFBR2、TNPO1、TOM1、TP53、TP53BP1、U2AF1、UPF3B、ZMYM2及ZNF814。 LUSC (肺小細胞癌)驅動子基因包括ABL2、ACAD8、ACO1、ACSL6、ACTG2、ACVR1B、ADAM10、AFF4、AQR、ARFGEF2、ARHGEF6、ARID1A、ARID1B、ARNTL、B2M、BLM、CASP8、CAST、CCAR1、CDC73、CDH1、CDKN1A、CDKN2A、CHD1L、CHD3、CHEK2、CIC、CLASP2、CLOCK、CNOT3、CNOT4、COPS2、CSDA、CSDE1、CTNNB1、CTTN、CUL1、DDX3X、DHX15、DHX9、DLG1、EEF1A1、EGFR、EIF2C3、EIF4A2、ELF1、ERBB2IP、EZH2、FGFR2、FGFR3、FMR1、FN1、FOXP1、FUBP1、FXR1、G3BP2、GATA3、GNAI1、GOLGA5、GPSM2、HLA-A、HLF、HRAS、HSP90AA1、HSP90AB1、HSPA8、IDH1、IREB2、IRS2、ITSN1、KDM5C、KEAP1、KRAS、MAP2K1、MAP3K1、MAP3K4、MED17、MED24、MEN1、MET、MKL1、MLH1、MLL、MLL2、MUC20、MYB、NCF2、NCK1、NDRG1、NF1、NFATC4、NFE2L2、NOTCH1、NR4A2、NTN4、NUP107、NUP98、PAX5、PCDH18、PCSK6、PHF6、PIK3CA、PIK3CB、PIK3R3、PIP5K1A、PPP2R5C、PRPF8、PTEN、PTPN11、RAD21、RASA1、RB1、RBM10、RGS3、RPL5、RTN4、SEC24D、SETD2、SETDB1、SF3A3、SF3B1、SIN3A、SMAD2、SMAD4、SPTAN1、SRGAP3、STAG1、STK11、STK4、SUZ12、SYNCRIP、TAOK2、TBL1XR1、TBX3、TFDP1、TFDP2、TGFBR2、THRAP3、TJP2、TNPO1、TOM1、TP53、UPF3B、WIPF1、WT1、ZC3H11A及ZFP36L2。 MB (神經管胚細胞瘤)驅動子基因包括ARID1A、ARID1B、ARID2、BCLAF1、BCOR、CCAR1、CREBBP、CTNNB1、DDX3X、FBXW7、FMR1、KDM6A、MGA、MLL2、MLL3、NF1、PIK3CA、PRKAR1A、PTCH1、SMARCA4、SMO、TAF1、TCF4及TP53。 MM (多發性骨髓瘤)驅動子基因包括APC、ARHGAP35、ARID2、BRAF、CASP8、CEP290、CHD9、DDX3X、FAM46C、FXR1、KRAS、MECOM、NF1、NRAS、NSD1、PIK3CA、SF3B1及TP53。 NB (神經母細胞瘤)驅動子基因包括AHR、ALK、ANK3、ARID1A、ATM、ATRX、CEP290、COL1A1、CREBBP、EIF2C3、KLF4、LRP6、MACF1、MECOM、MET、MLL2、MYCN、NF1、NOTCH1、NRAS、PBRM1、PIK3CA、PIK3CB、PTPN11、STAG1、TAF1及TRIO。 NSCLC (非小細胞肺癌)驅動子基因包括AKAP9、APC、HGF、KALRN、KEAP1、KRAS、MLL3、RB1、SEC24D、SMARCA4及TP53。 OV (卵巢癌)驅動子基因包括ACO1、ACTG1、AFF4、ARID1A、ASH1L、ASPM、ATF1、ATIC、ATR、ATRX、BAP1、BAZ2B、BMPR2、BRAF、BRCA1、BRCA2、CASP1、CCAR1、CCT5、CDK12、CHD1L、CHD4、CLASP2、CLSPN、CSDE1、CTNNB1、CUL2、DDX5、DLG1、DNMT3A、EIF2AK3、EIF4A2、ERBB2IP、F8、FAM123B、FBXW7、FLT3、FMR1、GNAS、GOLGA5、GPS2、HDAC3、HGF、HSP90AA1、ITSN1、KRAS、LPHN2、MAP3K4、MAP4K3、MECOM、MED12、MKL1、MLH1、MLL2、MYH10、NCKAP1、NDRG1、NF1、NOTCH1、NR4A2、NRAS、NSD1、PIK3CA、POLR2B、PTEN、RB1、RHOA、SETD2、SETDB1、SIN3A、SOS1、STAG1、STAG2、TBX3、TCF7L2、TFDP1、TGFBR2、TJP1、TOM1、TP53、TP53BP1、TRIO及YBX1。 PAAD (胰腺癌)驅動子基因包括ACVR1B、AHNAK、ANK3、ARHGAP35、ARID1A、ARID2、ATM、CREBBP、EP300、EPC1、KRAS、MAP2K4、MLL3、PBRM1、PCDH18、PCSK6、SF3B1、SMAD4、SMARCA4、TGFBR2及TP53。 PRAD (前列腺癌)驅動子基因包括ADCY1、AHNAK、AKAP9、APC、AQR、ARFGAP3、ARID1B、ATIC、ATM、ATRX、BCLAF1、BCOR、BNC2、BPTF、BRAF、CASP1、CAT、CDC27、CDH1、CDKN1B、CEP290、CHD1L、CHD3、CHD4、CHEK2、CNOT1、CNOT3、CNTNAP1、CTNNB1、CUL2、CUL3、EEF1B2、EGFR、EIF2AK3、EIF4G1、EP300、ERCC2、FAT1、FGFR2、FIP1L1、FN1、FRG1、G3BP2、GNAS、HGF、HNF1A、HRAS、HSP90AB1、HSPA8、IDH1、IRS2、KDM6A、KEAP1、MECOM、MED12、MLL2、MYH10、NAP1L1、NKX3-1、NOTCH1、NOTCH2、NUP98、PCDH18、PIK3CB、PLXNA1、PRPF8、PTEN、RPSAP58、SCAI、SETDB1、SMAD4、SMARCA1、SMARCB1、SPOP、SVEP1、TAOK2、TBL1XR1、TBX3、THRAP3、TJP1、TJP2、TP53、TP53BP1、TRIO、WHSC1L1、WNT5A、ZFHX3及ZNF814。 RCCC (腎透明細胞癌)驅動子基因包括ACO1、ACTG1、AHR、AKT1、ARHGAP26、ARID1A、ARID1B、ARID2、ASH1L、ATF1、ATM、BAP1、BCLAF1、BCOR、BMPR2、CAD、CAT、CCAR1、CDC73、CDH1、CHEK2、CLTC、CNOT3、CNOT4、COPS2、CSDA、CTCF、CUL1、DDX3X、DDX5、DHX15、DICER1、DIS3、EEF1A1、EGFR、EIF2AK3、EIF2C3、EIF4A2、EIF4G1、ELF1、ERBB2IP、EZH2、FAM123B、FLT3、FMR1、FUS、G3BP2、HDAC9、HLF、HNRPDL、HSP90AB1、IDH1、ITSN1、KDM5C、KDM6A、KEAP1、LCP1、LPHN2、LRP6、MAX、MED17、MED24、MET、MGA、MKL1、MLL3、MTOR、NCOR1、NFE2L2、NTN4、NUP98、PABPC1、PBRM1、PCDH18、PCSK6、PHF6、PIK3R1、PIP5K1A、PPP2R1A、PSMA6、PSME3、PTEN、RASA1、RPL22、RPL5、SEC24D、SETD2、SHMT1、SIN3A、SMAD2、SMC1A、SOX9、SRGAP3、TAOK2、TBL1XR1、TCF12、TJP1、TJP2、TP53BP1、TRIO、VHL、WHSC1L1、WT1、ZFP36L2及ZNF814。 SCLC (小細胞肺癌)驅動子基因包括AHNAK、AHR、AKAP9、ANK3、ARID1A、ARID1B、ARID2、ASH1L、ASPM、ATR、ATRX、BAZ2B、BCLAF1、BMPR2、BNC2、BRWD1、CCT5、CDK12、CHD1L、CHEK2、CLSPN、CREBBP、DICER1、EIF2AK3、EP300、FAM123B、FAT1、FN1、GNAS、HGF、HSP90AB1、ITSN1、KALRN、KDM6A、MED12、MLL、MLL2、MLL3、MNDA、MSR1、MTOR、MYB、NCKAP1、NF1、NOTCH1、NR4A2、NUP107、PIK3CA、PTEN、PTPRU、RAD21、RB1、SIN3A、SOS1、SOS2、SPTAN1、TAF1、TBX3、TJP1、TP53及ZC3H11A。 STAD (胃腺癌)驅動子基因包括ACAD8、ACSL6、ACTG2、ACVR1B、ACVR2A、ADAM10、AFF4、AKAP9、ANK3、APC、AQR、ARFGEF1、ARHGAP26、ARHGAP35、ARHGEF6、ARID1A、ARID1B、ARID4A、ASH1L、ATIC、ATP6AP2、ATR、ATRX、BAP1、BCOR、BPTF、BRAF、BRCA1、CAD、CAPN7、CASP8、CAT、CCAR1、CCT5、CDC73、CDH1、CDKN2A、CEP290、CHD1L、CHD3、CHEK2、CLASP2、CLOCK、CLTC、CNOT1、CNOT4、COL1A1、COPS2、CSDA、CSDE1、CSNK1G3、CTNNB1、CUL1、CUL2、CUL3、CYLD、DDX5、DHX15、DIS3、DLG1、DNMT3A、EEF1A1、EGFR、EIF2AK3、EIF4A2、EIF4G1、ELF3、EPHA1、ERBB2IP、ERCC2、EZH2、FAM123B、FAS、FGFR2、FLT3、FOXP1、FUBP1、G3BP2、GATA3、GNA11、GNAI1、GOLGA5、HDAC3、HLA-A、HLA-B、HNRPDL、HSP90AB1、IREB2、IRF2、IRS2、KDM6A、KLF4、KLF6、KRAS、LCP1、LPHN2、MACF1、MAP2K1、MAP2K4、MAP3K1、MECOM、MED12、MED17、MET、MKL1、MLH1、MSR1、MYH11、MYH9、NAP1L1、NCK1、NCKAP1、NEDD4L、NFE2L2、NR2F2、NR4A2、NSD1、NUP107、NUP98、PCSK5、PHF6、PIK3CA、PIK3CB、PIK3R1、PIP5K1A、POLR2B、PPP2R1A、PRRX1、PTEN、PTGS1、PTPN11、PTPRF、PTPRU、RAD21、RASA1、RBBP7、RBM5、RHOA、RPL22、RTN4、RUNX1、SETD2、SF3B1、SIN3A、SMAD2、SMAD4、SMARCA4、SMC1A、SOS1、SOS2、SOX9、SPOP、SRGAP3、STARD13、STIP1、STK4、SUZ12、TAF1、TAOK2、TBL1XR1、TBX3、TCF4、TCF7L2、TFDP1、THRAP3、TJP1、TJP2、TNPO1、TNPO2、TP53、TP53BP1、WIPF1、WT1、ZC3H11A及ZMYM2。 THCA (甲狀腺癌)驅動子基因包括AHNAK、AKAP9、ARHGAP26、ARID2、BPTF、BRAF、CDK12、CHD3、CTNNB1、DICER1、EIF1AX、GNAS、HNRPDL、HRAS、KRAS、LDHA、MLL、MLL3、NCK1、NRAS、NSD1、PIK3CA、PPM1D、PPP2R1A、PRPF8、PTEN、RPSAP58、TJP1、TP53、TRIO、WIPF1及ZC3H11A。 UCEC (子宮體子宮內膜樣癌)驅動子基因包括ACACA、ACTB、ACTG1、AHR、AKT1、ALK、ANK3、ARAP3、ARHGAP35、ARHGEF6、ARID1A、ARID5B、ARNTL、ATF1、ATIC、ATM、ATR、AXIN1、BAZ2B、BCLAF1、BMPR2、BRAF、BRCA1、CAPN7、CARM1、CAST、CAT、CCND1、CDKN1B、CHD3、CHD4、CHD9、CHEK2、CLOCK、CLTC、CNOT4、CSNK1G3、CTCF、CTNNB1、CTNND1、CUL1、CUX1、DEPDC1B、DHX15、DHX35、DICER1、DIS3、DNMT3A、EGFR、EIF1AX、EIF2AK3、EIF2C3、EIF4A2、EIF4G1、EP300、ERBB3、FAM123B、FAS、FBXW7、FGFR2、FLT3、FOXA2、FUBP1、FXR1、G3BP2、GNAI1、GPS2、GPSM2、HDAC3、HGF、IDH1、ING1、INPP4A、INPPL1、IREB2、KDM6A、KLF4、KRAS、MAP2K4、MAP3K1、MAX、MED17、MET、MGA、MKL1、MLH1、MLH3、MUC20、MYB、MYH10、NCF2、NCKAP1、NCOR1、NDRG1、NEDD4L、NF2、NFE2L2、NR2F2、NRAS、NUP93、PCDH18、PGR、PHF6、PIK3CA、PIK3R1、PIK3R3、PLCG1、PLXNB2、PPP2R1A、PPP2R5A、PPP2R5C、PRPF8、PRRX1、PTEN、PTPN11、RAD21、RAD23B、RBBP7、RBM5、RHEB、ROBO2、RPL22、RPL5、RTN4、RUNX1、SEC31A、SHMT1、SMAD2、SMC1A、SOX17、SPOP、SRGAP3、STIP1、SUZ12、SYNCRIP、TBL1XR1、TBX3、TFDP1、TGFBR2、TP53、TP53BP1、U2AF1、VHL、WIPF1、ZC3H11A、ZFHX3、ZFP36L2、ZMYM2及ZNF814。 在將經過濾新抗原決定基識別為癌症驅動子新抗原決定基後,可使用該癌症驅動子新抗原決定基之序列資訊製備一或多種免疫治療劑。在其他試劑中,尤其較佳的係,患者可用經核酸構築體遺傳修飾之病毒治療以引發對腫瘤之免疫反應,該核酸構築體使得表現經識別新抗原決定基中之至少一者。舉例而言,合適之病毒包括腺病毒、腺相關病毒、α病毒、疱疹病毒、慢病毒等。然而,腺病毒為尤其較佳的。此外,更佳的係病毒為複製缺陷型及非免疫原性病毒,其通常藉由所選擇病毒蛋白質(例如,E1、E3蛋白質)之靶向缺失來實現。此類所需特性可藉由使E2b基因功能缺失而進一步增強,且重組病毒之較高效價可使用如最近報告之經遺傳修飾之人類293細胞來達成(例如,J Virol
. 1998年二月;72(2): 926-933)。最典型地,所需核酸序列(用於經病毒感染細胞之表現)在此項技術中熟知之適當調節元件的控制下。無論重組病毒之類型為何,預期病毒可用於在活體外或活體內感染患者細胞(或非患者細胞)。舉例而言,病毒可經皮下或經靜脈內注射以如此感染患者抗原呈遞細胞。替代地,免疫勝任細胞(例如,NK細胞、T細胞、巨噬細胞、樹突狀細胞等)可經活體外感染且接著輸注至患者。替代地,免疫療法不必依賴於病毒,但可使用核酸接種疫苗或引起新抗原決定基(例如,作為單一肽、串聯微基因等)在所需細胞中表現的其他重組載體,且尤其免疫勝任細胞來實現。 同樣地,亦認為除(病毒)表現載體外之其他免疫治療劑為合適的,且包括表現與癌症驅動子新抗原決定基具有親和力的嵌合抗原受體,或與特異性結合至癌症驅動子新抗原決定基之抗體具有親和力的高親和性CD16受體的經遺傳工程改造之細胞(且尤其各種免疫勝任細胞)。舉例而言,所預期免疫治療劑包括NK細胞(例如,aNK細胞、haNK細胞或taNK細胞,可購自NantKwest, 9920 Jefferson Blvd. Culver City,CA 90232)或經遺傳修飾之T細胞(例如,表現T細胞受體)或經HLA匹配之患者特異性及癌症特異性新抗原決定基活體外刺激之T細胞。 替代地,癌症驅動子新抗原決定基亦可以肽之形式投與,該等肽視情況結合至載體蛋白質以如此充當癌症疫苗。在其他預期態樣中,癌症驅動子新抗原決定基亦可用於製備與癌症驅動子新抗原決定基特異性結合之抗體。此類抗體可為人源性抗體、人源化抗體或完全合成性抗體,如WO 2016/172722中所描述。 此外,亦應認識到,在將新抗原決定基識別為癌症驅動子新抗原決定基之後,可選擇靶向由含有該癌症驅動子新抗原決定基之癌症驅動子基因編碼之蛋白質的藥物。舉例而言,在癌症驅動子基因編碼受體時,可投與針對該受體(或其配位體)之受體拮抗劑或抑制劑或抗體,其對該受體具有特異性。類似地,在癌症驅動子基因編碼激酶時,可向患者投與激酶抑制劑。因此,應瞭解,癌症驅動子新抗原決定基之識別可提供組合治療選擇方案,該方案使用免疫系統及突變蛋白質之功能靶向突變蛋白質。 因此,本發明人亦預期一種將包括偶合至以下各者之載劑的免疫治療組合物:(i)與患者特異性癌症驅動子新抗原決定基具有結合特異性之合成性抗體、(ii)合成性患者特異性癌症驅動子新抗原決定基、(iii)編碼患者特異性癌症驅動子新抗原決定基之核酸,或(iv)與患者特異性癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體。舉例而言,在免疫治療組合物經調配為疫苗之情況下,載劑將通常包含單一載體蛋白質(例如,KLH或白蛋白)或適用於疫苗接種的醫藥學上可接受之聚合物。在另一方面,在免疫治療組合物用作基於細胞或病毒之組合物時,載劑將通常包括免疫勝任細胞(例如,CD8+ T細胞、樹突狀細胞或NK細胞)或包括編碼癌症驅動子新抗原決定基之核酸的重組病毒(例如,腺病毒)。如在此項技術中習用,免疫治療組合物將大體上包括適合於注射或輸注的醫藥學上可接受之載劑。實例
資料集:如下文所指示之各種癌症的TCGA WGS及RNAseq資料係下載自加利福尼亞大學聖塔克魯斯(UCSC)癌症基因組中心(https://cghub.ucsc.edu/)。基於完整WGS資料之可用性選擇TCGA樣品以有助於計算機HLA分型。在可用時使用相應樣品之RNAseq資料。 腫瘤變異體及新抗原決定基之識別:藉由腫瘤及正常樣品之定位引導同步比對使用BAM檔案以基本上如US 2012/0059670A1及US 2012/0066001A1中所揭示之方式識別單一核苷酸變異體(SNV)及插入/缺失(插入缺失)。由於HLA-A對偶基因主要結合至9聚體肽片段,因此本發明人專注於識別9聚體新抗原決定基。藉由產生來源於經識別SNV或插入缺失的9聚體胺基酸鏈的全部可能排列(亦即,各9聚體在特有位置處具有經改變胺基酸)來識別新抗原決定基。作為降低特定新抗原決定基之可能脫靶效應的手段,本發明人過濾針對自每一已知人類基因產生之全部可能9聚體肽序列的所有經識別新抗原決定基。此外,本發明人亦自dbSNP (URL: www.ncbi.nlm.nih.gov/SNP/)過濾單核苷酸多形現象以顧及定序資料內可能已丟失之罕見蛋白質序列。新抗原決定基藉由RNA表現以及藉由所觀測之編碼變異體的對偶基因頻率進一步分級以補償由腫瘤不均勻性引起之問題。 HLA分型:HLA分型資料不可用於TCGA樣品;因此,本發明人使用WGS、RNAseq資料及基本上如PCT/US16/48768中所描述之HLA森林演算法進行計算機HLA分型。簡言之,Burrows-Wheeler比對演算法用以將定序讀數與IMGT/HLA資料庫內之每一不同HLA對偶基因進行比對(URL: www.ebi.ac.uk/ipd/imgt/hla/)。考慮讀數質量得分,基於鹼基之保留給每一比對評分。各HLA對偶基因將隨後具有考慮各讀數在多大程度上與某一HLA對偶基因對準之得分總和,且選擇具有最高得分之對偶基因作為初級對偶基因分型。接著藉由移除與初級對偶基因分型較佳對準之讀數來進行二級對偶基因分型,且接著在不比對初級對偶基因的情況下對後續讀數再評分。使用此方法,本發明人對所有樣品獲得HLA-A、HLA-B、HLA-C及HLA-DRB1之至少4位數之水準的分型結果。 新抗原決定基-HLA親和力測定:NetMHC 3.4 (URL: www.cbs.dtu.dk/services/NetMHC-3.4/)用以預測新抗原決定基是否將結合至特異性HLA對偶基因。為降低複雜度空間,本發明人選擇限制對HLA-A對偶基因之結合分析,此係因為其為最佳表徵之HLA對偶基因且具有最好結合親和力模型。由於NetMHC 3.4工具不具有每一經識別HLA-A對偶基因的模型,因此若患者之HLA-A分型在NetMHC 3.4中不可使用,則選擇HLA超類型用於結合預測。保留具有預測結合親和力< 500 nM蛋白濃度之新抗原決定基用於進一步分析。然而,亦認為其他更嚴格之結合標準(< 250 nM,或< 150 nM,或< 50 nM)為適當的。 在癌症類型中之編碼突變及新抗原決定基負載:WGS資料及相應RNAseq資料(在可用時)用於確立如圖 1
中所展示之23種癌症分類中的750個患者樣品之編碼DNA的潛在新抗原決定基及每兆鹼基之體細胞編碼變異體的基線。在此處,展示TCGA內之23種癌症分類中的750個患者樣品之新抗原決定基及變異體計數。上圖展示新抗原決定基計數,同時低位組展示變異體計數。Y軸展示編碼DNA之每兆鹼基之計數(88 MB用於人類基因組集合(hg)19)。X軸藉由括弧中展示之患者樣品數展示各癌症分類。藉由方塊指示中值樣品計數。下文之餅圖表顯示新抗原決定基及正常抗原決定基(在此處:可見於匹配正常組織或已知SNP資料庫)在所有癌症類型內之百分比。 如可輕易自圖1獲得,在不同癌症類型中,突變負載及新抗原決定基負載不同,且黑素瘤及鱗狀細胞肺癌具有最高新抗原決定基負載且甲狀腺癌及急性骨髓白血病具有最低新抗原決定基負載。過濾抗已知人類序列之資料庫的假定新抗原決定基以移除僅10%經識別之新抗原決定基映射至已知蛋白質之片段所揭露之潛在脫靶效應;因此,大部分突變體產生特有的蛋白質序列。然而,儘管特有新抗原決定基之百分率相對較高,但不能假定出現表現及呈現。實際上,如下文更詳細地進一步展示,應認識到,經表現及呈現之新抗原決定基的數目大大低於僅藉由定序所識別之新抗原決定基的數目。 使用上文所論述之TCGA資料集及方法,本發明人藉由腫瘤對比正常(DNA+)、表現之腫瘤對比正常(DNA+、RNA+)及表現且HLA匹配之腫瘤對比正常(DNA+、RNA+、netMHC+)過濾新抗原決定基。在此處,本發明人限制對含有在北美以高頻率出現之HLA-A*02:01對偶基因之樣品的分析。值得注意地,且如圖 2
中所示之圖解,經預測之新抗原決定基、表現之新抗原決定基及具有與HLA-A*02:01之親和力的新抗原決定基的數目分別為211,285、89,351及1,732。對於不同樣品大小進行修正,經預測之新抗原決定基、表現之新抗原決定基及具有與HLA-A*02:01之親和力的新抗原決定基的平均數目分別為23,272、9,619及138。接著使用如上文所描述之已知癌症驅動子基因集合來分析未經過濾的及經過濾的新抗原決定基在所需基因型(在此處:癌症驅動子基因)內之定位。引起關注地,且如圖2之餅狀圖中所展示,在全部癌症中,僅6%之新抗原決定基出現在癌症驅動子基因中,其進一步有助於將其他困惑地較大數目之潛在靶向物降低至相對較低數目之具有潛在高影響之靶向物。此外,尤其在經過濾之新抗原決定基的數目相對較低的情況下,癌症驅動新抗原決定基之識別將提供選擇用於以其他方式未實現之治療的新抗原決定基的機會。 本文中值的範圍之敍述僅意欲充當個別地提及屬於該範圍內之各單獨值的簡寫方法。除非本文中另外指示,否則每一個別值併入至本說明書中,如同其在本文中個別地敍述一般。除非本文中另外指示或與上下文明顯矛盾,否則本文所描述之所有方法均可以任何適合的順序進行。相對於本文某些實施例提供之任何及全部實例,或例示性語言(例如,「諸如」)之用途僅意欲更好闡明本發明且並不對以其他方式所主張之本發明之範疇造成限制。本說明書中之語言不應理解為指示任何未主張之要素對於實踐本發明必不可少。 一般熟習此項技術者應顯而易見的係除已經描述之彼等修飾之外的更多修飾可能未脫離本文之發明性概念。因此,本發明性主題除在所附權利要求書之範疇內外並不受限。此外,在解釋本說明書及權利要求兩者中,所有術語應以與上下文一致之最廣泛可能的方式解釋。特定言之,術語「包含(comprises/comprising)」應解釋為指代非排他性方式中之元素、組份或步驟,指示該等引用元素、組分或步驟可存在,或利用,或與其他元素、組分或未明確引用之步驟組合。在本說明書權利要求係關於選自由A、B、C…及N組成之群的一些中之至少一者時,本文應解釋為僅需要該群中之一個元素,而非A加N,或B加N等。
圖1為各種癌症中之新抗原決定基頻率及編碼變異體頻率之例示性圖形表示,以及各種癌症中之獨特的新抗原決定基之頻率之圖形表示。 圖2為各種癌症之HLA匹配之新抗原決定基之頻率的例示性圖形表示,以及癌症驅動基因內之獨特新抗原決定基之頻率的圖形表示。
Claims (68)
- 一種選擇用於癌症之免疫療法之新抗原決定基的方法,其包含: 自患者獲得來自腫瘤組織及匹配正常組織之組學資料,且使用該組學資料,來判定複數個基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基; 根據該患者之HLA類型過濾該等基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基,從而獲得HLA匹配之新抗原決定基;以及 根據受到該等HLA匹配之新抗原決定基影響之基因類型來過濾該等HLA匹配之新抗原決定基,從而獲得癌症驅動子新抗原決定基。
- 如請求項1之方法,其中該組學資料包含選自由以下組成之群的至少兩種組學資料:全基因組定序資料、全外顯子組定序資料、RNAseq資料及定量蛋白質組資料。
- 如前述請求項中任一項之方法,其中測定該複數個基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基之該步驟包含來自該腫瘤組織及該匹配正常組織之組學資料的定位引導同步比對。
- 如前述請求項中任一項之方法,其進一步包含根據選自由以下組成之群的先驗已知分子變異中之至少一者來過濾該等基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基的步驟:單核苷酸多形現象、短缺失及插入多形現象、微衛星標記、短串聯重複、異型接合序列、多核苷酸多形現象及指定變異體。
- 如前述請求項中任一項之方法,其中該腫瘤組織為實體腫瘤組織且其中該匹配正常組織為血液。
- 如前述請求項中任一項之方法,其中根據HLA類型過濾該等新抗原決定基之該步驟係使用複數個不同個別新抗原決定基序列針對該等新抗原決定基中之每一者進行,其中經改變胺基酸在該新抗原決定基序列內具有不同位置。
- 如請求項6之方法,其中該等個別新抗原決定基序列具有介於7個至20個胺基酸之間的長度。
- 如前述請求項中任一項之方法,其中根據HLA類型過濾之該步驟包含根據該患者組學資料判定該HLA類型。
- 如前述請求項中任一項之方法,其中根據HLA類型過濾之該步驟進行至至少4位數之深度。
- 如請求項1之方法,其中根據HLA類型過濾之步驟包含測定該等新抗原決定基與該患者之至少一種MHC I類子型及至少一種MHC II類子型的親和力。
- 如請求項1之方法,其中該等HLA匹配之新抗原決定基與該患者之至少一種MHC I類子型或至少一種MHC II類子型之親和力等於或小於150 nM。
- 如前述請求項中任一項之方法,其中該受影響基因類型為選自由以下組成之群的癌症之癌症驅動子基因:ALL、AML、BLCA、BRCA、CLL、CM、COREAD、ESCA、GBM、HC、HNSC、LUAD、LUSC、MB、NB、NSCLC、OV、PRAD、RCCC、SCLC、STAD、THCA及UCEC。
- 如前述請求項中任一項之方法,其中該受影響基因類型為表1中所列出之癌症驅動子基因。
- 如前述請求項中任一項之方法,其進一步包含判定該受影響基因類型中之功能失常的步驟。
- 如前述請求項中任一項之方法,其進一步包含產生對靶向由該受影響基因類型編碼之蛋白質的非免疫治療藥物之建議的步驟。
- 如前述請求項中任一項之方法,其進一步包含使用該癌症驅動子新抗原決定基來製備免疫治療劑之步驟。
- 如請求項16之方法,其中該免疫治療劑包含以下中之至少一者:與該癌症驅動子新抗原決定基具有結合特異性之合成性抗體、合成性癌症驅動子新抗原決定基、編碼該癌症驅動子新抗原決定基之核酸、攜載與該癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體的免疫勝任細胞,及包含編碼該癌症驅動子新抗原決定基之核酸的重組型病毒。
- 如請求項1之方法,其中測定該複數個基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基的步驟包含來自該腫瘤組織及該匹配正常組織之組學資料的定位引導同步比對。
- 如請求項1之方法,其進一步包含根據選自由以下組成之群的先驗已知分子變異中之至少一者來過濾該等基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基的步驟:單核苷酸多形現象、短缺失及插入多形現象、微衛星標記、短串聯重複、異型接合序列、多核苷酸多形現象及指定變異體。
- 如請求項1之方法,其中該腫瘤組織為實體腫瘤組織且其中該匹配正常組織為血液。
- 如請求項1之方法,其中根據HLA類型過濾該等新抗原決定基之該步驟係使用複數個不同個別新抗原決定基序列針對該等新抗原決定基中之每一者進行,其中經改變胺基酸在該新抗原決定基序列內具有不同位置。
- 如請求項21之方法,其中該等個別新抗原決定基序列具有介於7個至20個胺基酸之間的長度。
- 如請求項1之方法,其中根據HLA類型過濾之該步驟包含根據該患者組學資料判定該HLA類型。
- 如請求項1之方法,其中根據HLA類型過濾之該步驟進行至至少4位數之深度。
- 如請求項1之方法,其中根據HLA類型過濾之該步驟包含測定該等新抗原決定基與該患者之至少一種MHC I類子型及至少一種MHC II類子型的親和力。
- 如請求項1之方法,其中該等HLA匹配之新抗原決定基與該患者之至少一種MHC I類子型或至少一種MHC II類子型之親和力等於或小於150 nM。
- 如請求項1之方法,其中該受影響基因類型為選自由以下組成之群的癌症之癌症驅動子基因:ALL、AML、BLCA、BRCA、CLL、CM、COREAD、ESCA、GBM、HC、HNSC、LUAD、LUSC、MB、NB、NSCLC、OV、PRAD、RCCC、SCLC、STAD、THCA及UCEC。
- 如請求項1之方法,其中該受影響基因類型為表1中所列出之癌症驅動子基因。
- 如請求項1之方法,其進一步包含判定該受影響基因類型中之功能失常的步驟。
- 如請求項1之方法,其進一步包含產生對靶向由該受影響基因類型編碼之蛋白質的非免疫治療藥物之建議的步驟。
- 如請求項1之方法,其進一步包含使用該癌症驅動子新抗原決定基來製備免疫治療劑之步驟。
- 如請求項31之方法,其中該免疫治療劑包含以下中之至少一者:與該癌症驅動子新抗原決定基具有結合特異性之合成性抗體、合成性癌症驅動子新抗原決定基、編碼該癌症驅動子新抗原決定基之核酸、攜載與該癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體的免疫勝任細胞,及包含編碼該癌症驅動子新抗原決定基之核酸的重組病毒。
- 一種使用免疫療法治療患者之癌症的方法,其包含: 自患者獲得來自腫瘤組織及匹配正常組織之組學資料,且使用該組學資料來判定複數個基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基; 自該等基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基衍生癌症驅動子新抗原決定基;以及 向該患者投與包含以下中之至少一者的免疫治療劑:與該癌症驅動子新抗原決定基具有結合特異性之合成性抗體、合成性癌症驅動子新抗原決定基、編碼該癌症驅動子新抗原決定基之核酸、攜載與該癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體的免疫勝任細胞,及包含編碼該癌症驅動子新抗原決定基之核酸的重組病毒。
- 如請求項33之方法,其中該組學資料包含選自由以下組成之群的至少兩種組學資料:全基因組定序資料、全外顯子組定序資料、RNAseq資料及定量蛋白質組資料。
- 如請求項33至34中任一項之方法,其中測定該複數個基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基之該步驟包含來自該腫瘤組織及該匹配正常組織之組學資料的定位引導同步比對。
- 如請求項33至35中任一項之方法,其進一步包含根據選自由以下組成之群的先驗已知分子變異中之至少一者來過濾該等基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基的步驟:單核苷酸多形現象、短缺失及插入多形現象、微衛星標記、短串聯重複、異型接合序列、多核苷酸多形現象及指定變異體。
- 如請求項33至36中任一項之方法,其中該腫瘤組織為實體腫瘤組織且其中該匹配正常組織為血液。
- 如請求項33至37中任一項之方法,其中衍生該癌症驅動子新抗原決定基之該步驟包含根據該患者之HLA類型來過濾該等患者特異性及腫瘤特異性新抗原決定基的步驟。
- 如請求項38之方法,其中根據HLA類型過濾之該步驟使用複數個不同個別新抗原決定基序列,其中經改變胺基酸在該新抗原決定基序列內具有不同位置,且其中該等個別新抗原決定基序列具有介於7個至20個胺基酸之間的長度。
- 如請求項38至39中任一項之方法,其中根據HLA類型過濾之該步驟包含根據該患者組學資料判定該HLA類型。
- 如請求項38至40中任一項之方法,其中根據HLA類型過濾之該步驟進行至至少4位數之深度。
- 如請求項38至41中任一項之方法,其中根據HLA類型過濾之該步驟包含測定該等新抗原決定基與該患者之至少一種MHC I類子型及至少一種MHC II類子型的親和力。
- 如請求項33至42中任一項之方法,其中該癌症驅動子新抗原決定基位於選自由以下組成之群的基因中:ALL、AML、BLCA、BRCA、CLL、CM、COREAD、ESCA、GBM、HC、HNSC、LUAD、LUSC、MB、NB、NSCLC、OV、PRAD、RCCC、SCLC、STAD、THCA及UCEC。
- 如請求項33至42中任一項之方法,其中該癌症驅動子基因列於表1中。
- 如請求項33至44中任一項之方法,其進一步包含投與靶向包含該癌症驅動子新抗原決定基之蛋白質之非免疫治療藥物的步驟。
- 如請求項33之方法,其中判定該複數個基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基的該步驟包含來自該腫瘤組織及該匹配正常組織之組學資料的定位引導同步比對。
- 如請求項33之方法,其進一步包含根據選自由以下組成之群的先驗已知分子變異中之至少一者來過濾該等基於所表現錯義之患者特異性及腫瘤特異性新抗原決定基的步驟:單核苷酸多形現象、短缺失及插入多形現象、微衛星標記、短串聯重複、異型接合序列、多核苷酸多形現象及指定變異體。
- 如請求項33之方法,其中該腫瘤組織為實體腫瘤組織且其中該匹配正常組織為血液。
- 如請求項33之方法,其中衍生該癌症驅動子新抗原決定基之該步驟包含根據該患者之HLA類型過濾該等患者特異性及腫瘤特異性新抗原決定基的步驟。
- 如請求項49之方法,其中根據HLA類型過濾之該步驟使用複數個不同個別新抗原決定基序列,其中經改變胺基酸在該新抗原決定基序列內具有不同位置,且其中該等個別新抗原決定基序列具有介於7個至20個胺基酸之間的長度。
- 如請求項49之方法,其中根據HLA類型過濾之該步驟包含自該患者組學資料判定該HLA類型。
- 如請求項49之方法,其中根據HLA類型過濾之該步驟進行至至少4位數之深度。
- 如請求項49之方法,其中根據HLA類型過濾之該步驟包含測定該等新抗原決定基與該患者之至少一種MHC I類子型及至少一種MHC II類子型的親和力。
- 如請求項33之方法,其中該癌症驅動子新抗原決定基位於選自由以下組成之群的基因中:ALL、AML、BLCA、BRCA、CLL、CM、COREAD、ESCA、GBM、HC、HNSC、LUAD、LUSC、MB、NB、NSCLC、OV、PRAD、RCCC、SCLC、STAD、THCA及UCEC。
- 如請求項33之方法,其中該癌症驅動子基因列於表1中。
- 如請求項33之方法,其進一步包含投與靶向包含該癌症驅動子新抗原決定基之蛋白質之非免疫治療藥物的步驟。
- 一種免疫治療組合物,其包含: 載劑,其偶合至(i)與患者特異性癌症驅動子新抗原決定基具有結合特異性之合成性抗體、(ii)合成性患者特異性癌症驅動子新抗原決定基、(iii)編碼該患者特異性癌症驅動子新抗原決定基之核酸,或(iv)與該患者特異性癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體。
- 如請求項57之免疫治療組合物,其中該載劑包含單一蛋白質或包含醫藥學上可接受之聚合物。
- 如請求項57之免疫治療組合物,其中該載劑為免疫勝任細胞。
- 如請求項59之免疫治療組合物,其中該免疫勝任細胞為CD8+ T細胞或NK細胞。
- 如請求項57之免疫治療組合物,其中該載劑為重組病毒。
- 如請求項57之免疫治療組合物,其進一步包含適合於注射或輸注之醫藥學上可接受之載劑。
- 一種免疫治療劑之用途,其係用於治療癌症,其中該免疫治療劑包含以下中之至少一者:與患者特異性癌症驅動子新抗原決定基具有結合特異性之合成性抗體、合成性患者特異性癌症驅動子新抗原決定基、編碼患者特異性癌症驅動子新抗原決定基之核酸、攜載與患者特異性癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體的免疫勝任細胞,及包含編碼患者特異性癌症驅動子新抗原決定基之核酸的重組病毒。
- 如請求項63之用途,其中該合成性抗體偶合至NK細胞或偶合至包含單一蛋白質或包含醫藥學上可接受之聚合物的載劑。
- 如請求項63之用途,其中患者特異性合成性癌症驅動子新抗原決定基偶合至包含單一蛋白質或包含醫藥學上可接受之聚合物的載劑。
- 如請求項63之用途,其中編碼該患者特異性癌症驅動子新抗原決定基之該核酸包含於免疫勝任細胞或病毒中,或偶合至包含單一蛋白質或包含醫藥學上可接受之聚合物的載劑。
- 一種重組免疫勝任細胞,其包含編碼與患者特異性癌症驅動子新抗原決定基具有結合特異性之嵌合抗原受體或編碼該患者特異性癌症驅動子新抗原決定基之核酸。
- 如請求項67之重組免疫勝任細胞,其中該免疫勝任細胞為CD8+ T細胞或NK細胞,或NK92衍生物。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662294665P | 2016-02-12 | 2016-02-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW201739919A true TW201739919A (zh) | 2017-11-16 |
Family
ID=59564011
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW106104528A TW201739919A (zh) | 2016-02-12 | 2017-02-10 | 患者特異性新抗原決定基之高通量識別以作為用於癌症免疫療法之治療劑 |
Country Status (12)
Country | Link |
---|---|
US (2) | US11361841B2 (zh) |
EP (1) | EP3414692A4 (zh) |
JP (1) | JP2019511907A (zh) |
KR (1) | KR20180091119A (zh) |
CN (1) | CN108701172A (zh) |
AU (1) | AU2017217877A1 (zh) |
CA (1) | CA3014252A1 (zh) |
IL (1) | IL261090A (zh) |
MX (1) | MX2018009804A (zh) |
SG (1) | SG11201806282XA (zh) |
TW (1) | TW201739919A (zh) |
WO (1) | WO2017139694A1 (zh) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2017217877A1 (en) | 2016-02-12 | 2018-08-16 | Nant Holdings Ip, Llc | High-throughput identification of patient-specific neoepitopes as therapeutic targets for cancer immunotherapies |
CA3074734A1 (en) | 2017-09-06 | 2019-03-14 | Nant Holdings Ip, Llc | Hla tissue matching and methods therefor |
WO2019060835A2 (en) * | 2017-09-25 | 2019-03-28 | Nant Holdings Ip, Llc | VALIDATION OF PRESENTATION OF NEO-EPITOPE |
US11793867B2 (en) | 2017-12-18 | 2023-10-24 | Biontech Us Inc. | Neoantigens and uses thereof |
US20210106574A1 (en) * | 2017-12-27 | 2021-04-15 | Tesaro, Inc. | Methods of Treating Cancer |
CN109021062B (zh) * | 2018-08-06 | 2021-08-20 | 倍而达药业(苏州)有限公司 | 一种肿瘤新抗原的筛选方法 |
WO2020033585A1 (en) * | 2018-08-07 | 2020-02-13 | The Broad Institute, Inc. | Methods for combinatorial screening and use of therapeutic targets thereof |
KR20210093251A (ko) * | 2018-10-16 | 2021-07-27 | 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 | 암 및 다른 질환의 진단 및 치료를 위한 병원성 세포외 매트릭스의 동정 및 표적화 |
GB201817651D0 (en) * | 2018-10-29 | 2018-12-12 | Univ College Dublin Nat Univ Ireland Dublin | Method for predicting effectiveness of treatments for cancer patients |
WO2020092038A1 (en) * | 2018-10-31 | 2020-05-07 | Nantomics, Llc | Cdkn2a screening germline expression |
CN109438570B (zh) * | 2018-11-28 | 2021-07-20 | 生命谷(海南)生物科技股份有限公司 | 肿瘤相关基因fgfr3突变短肽及其应用 |
US20220296642A1 (en) * | 2018-12-04 | 2022-09-22 | Nantomics, Llc | Methods of Making Therapeutic T Lymphocytes |
WO2020176726A1 (en) * | 2019-02-27 | 2020-09-03 | Epivax Oncology, Inc. | Improved compositions and methods for personalized neoplasia vaccines |
CN110286235B (zh) * | 2019-07-10 | 2022-07-15 | 郑州大学 | 一种用于肝癌早期筛查和诊断的联合检测血清标志物、试剂盒及检测方法 |
US20230047716A1 (en) * | 2020-01-07 | 2023-02-16 | Korea Advanced Institute Of Science And Technology | Method and system for screening neoantigens, and uses thereof |
CN112980948B (zh) * | 2020-08-28 | 2023-03-21 | 中山大学附属口腔医院 | Nfat3作为治疗靶点在筛选或制备头颈部鳞状细胞癌药物中的应用 |
CN112725454B (zh) * | 2021-02-03 | 2021-08-03 | 山东第一医科大学附属省立医院(山东省立医院) | 膀胱癌患者总体生存率预后模型 |
CN113755594B (zh) * | 2021-09-26 | 2024-05-14 | 中国医学科学院肿瘤医院 | 一种预测小细胞肺癌辅助化疗获益和识别化疗耐药治疗靶点的系统和应用 |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8614169B2 (en) * | 2001-12-04 | 2013-12-24 | Wayne State University | Neoepitope detection of disease using protein arrays |
US9575070B2 (en) * | 2001-12-04 | 2017-02-21 | Wayne State University | Neoepitope detection of disease using protein arrays |
US7664689B1 (en) | 2003-06-24 | 2010-02-16 | Evercom Systems, Inc. | Systems and methods for transaction and information management |
WO2003106589A1 (en) * | 2002-06-13 | 2003-12-24 | Lyotropic Therapeutics, Inc. | A nanoporous particle with a retained target |
AU2003295502A1 (en) * | 2002-11-12 | 2004-06-03 | Yucheng Chang | Adenoviral vector vaccine |
DK1601450T3 (da) | 2003-03-10 | 2013-09-08 | Expression Pathology Inc | Flydende vævspræparat ud fra histopatologisk bearbejdede biologiske prøver, væv og celler |
KR101289774B1 (ko) * | 2004-03-31 | 2013-08-07 | 다나-파버 캔서 인스티튜트 인크. | 표피성장인자 수용체를 표적으로 하는 치료에 대한 암의반응성을 결정하는 방법 |
WO2006007667A1 (en) * | 2004-07-23 | 2006-01-26 | The Walter And Eliza Hall Institute Of Medical Research | Therapeutic and diagnostic agents |
WO2006108241A1 (en) * | 2005-04-14 | 2006-10-19 | The University Of Queensland | Immunomodulating compositions and uses therefor |
BR112012029066A2 (pt) * | 2010-05-14 | 2020-09-01 | The General Hospital Corporation | composições e processos de identificação de neoantígenos específicos de tumor. |
CN103384887B (zh) | 2010-05-25 | 2017-01-18 | 加利福尼亚大学董事会 | Bambam:高通量测序数据的平行比较分析 |
US9646134B2 (en) | 2010-05-25 | 2017-05-09 | The Regents Of The University Of California | Bambam: parallel comparative analysis of high-throughput sequencing data |
CN103079589A (zh) * | 2010-08-23 | 2013-05-01 | 西莱克塔生物科技公司 | 用于诱导对抗原的免疫应答的靶向多表位剂型 |
EP3511425A1 (en) * | 2012-07-12 | 2019-07-17 | Persimmune, Inc. | Personalized cancer vaccines and adoptive immune cell therapies |
CA2878843A1 (en) * | 2012-07-13 | 2014-01-16 | Zymeworks Inc. | Bispecific asymmetric heterodimers comprising anti-cd3 constructs |
KR102341899B1 (ko) * | 2013-04-07 | 2021-12-21 | 더 브로드 인스티튜트, 인코퍼레이티드 | 개인맞춤화 신생물 백신을 위한 조성물 및 방법 |
AU2014368898B2 (en) * | 2013-12-20 | 2020-06-11 | Dana-Farber Cancer Institute, Inc. | Combination therapy with neoantigen vaccine |
CN108513593A (zh) * | 2015-04-23 | 2018-09-07 | 南托米克斯有限责任公司 | 癌症新表位 |
US20170017749A1 (en) | 2015-07-15 | 2017-01-19 | International Business Machines Corporation | System and method for identifying cancer driver genes |
KR102211461B1 (ko) | 2015-08-25 | 2021-02-03 | 난토믹스, 엘엘씨 | 고-정확도 변이 판정을 위한 시스템들 및 방법들 |
KR20240010089A (ko) * | 2015-10-12 | 2024-01-23 | 난토믹스, 엘엘씨 | 네오에피토프의 반복적 발견 및 이에 대한 적응성 면역치료 및 방법 |
EP3362930A4 (en) | 2015-10-12 | 2019-06-19 | Nantomics, LLC | SYSTEMS, COMPOSITIONS, AND METHODS FOR DISCOVERING MSI AND NEOEPPITOPES THAT PROVIDE SENSITIVITY TO IMMUNE CONTROL POINTS |
AU2017217877A1 (en) | 2016-02-12 | 2018-08-16 | Nant Holdings Ip, Llc | High-throughput identification of patient-specific neoepitopes as therapeutic targets for cancer immunotherapies |
-
2017
- 2017-02-10 AU AU2017217877A patent/AU2017217877A1/en not_active Abandoned
- 2017-02-10 TW TW106104528A patent/TW201739919A/zh unknown
- 2017-02-10 US US16/073,105 patent/US11361841B2/en active Active
- 2017-02-10 MX MX2018009804A patent/MX2018009804A/es unknown
- 2017-02-10 SG SG11201806282XA patent/SG11201806282XA/en unknown
- 2017-02-10 JP JP2018542278A patent/JP2019511907A/ja active Pending
- 2017-02-10 EP EP17750909.8A patent/EP3414692A4/en not_active Withdrawn
- 2017-02-10 KR KR1020187022527A patent/KR20180091119A/ko not_active Application Discontinuation
- 2017-02-10 CN CN201780011208.5A patent/CN108701172A/zh active Pending
- 2017-02-10 CA CA3014252A patent/CA3014252A1/en not_active Abandoned
- 2017-02-10 WO PCT/US2017/017549 patent/WO2017139694A1/en active Application Filing
-
2018
- 2018-08-09 IL IL261090A patent/IL261090A/en unknown
-
2022
- 2022-05-09 US US17/740,040 patent/US20220270709A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
JP2019511907A (ja) | 2019-05-09 |
EP3414692A4 (en) | 2020-07-29 |
US20190034582A1 (en) | 2019-01-31 |
IL261090A (en) | 2018-10-31 |
CN108701172A (zh) | 2018-10-23 |
MX2018009804A (es) | 2018-11-09 |
US11361841B2 (en) | 2022-06-14 |
SG11201806282XA (en) | 2018-08-30 |
EP3414692A1 (en) | 2018-12-19 |
US20220270709A1 (en) | 2022-08-25 |
KR20180091119A (ko) | 2018-08-14 |
AU2017217877A1 (en) | 2018-08-16 |
WO2017139694A1 (en) | 2017-08-17 |
CA3014252A1 (en) | 2017-08-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20220270709A1 (en) | High-Throughput Identification of Patient-Specific Neoepitopes as Therapeutic Targets for Cancer Immunotherapies | |
US20220282322A1 (en) | Individualized vaccines for cancer | |
US20230190898A1 (en) | Individualized vaccines for cancer | |
US20220165353A1 (en) | Tumor antigenicity processing and presentation | |
US20240079089A1 (en) | Immunotherapy Markers And Uses Therefor | |
JP2018532736A (ja) | チェックポイント阻害物質への感受性を予測するmsiおよびネオエピトープの探索のための系、組成物、および方法 | |
KR20220111246A (ko) | 순환 뉴클레오솜을 단리하는 방법 | |
TWI845506B (zh) | 使用腫瘤抗原特異性t細胞之癌症治療的方法 | |
Leprieur et al. | Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression | |
KR20190032374A (ko) | 엑소좀-안내 암 치료(exosome-guided treatment of cancer) | |
WO2023284736A1 (en) | Biomarkers for colorectal cancer treatment | |
EP3473267B1 (en) | Individualized vaccines for cancer |