CN118207335A - 一种与抗肿瘤药物引起的副作用相关的snp标志物及其用途 - Google Patents
一种与抗肿瘤药物引起的副作用相关的snp标志物及其用途 Download PDFInfo
- Publication number
- CN118207335A CN118207335A CN202410493670.5A CN202410493670A CN118207335A CN 118207335 A CN118207335 A CN 118207335A CN 202410493670 A CN202410493670 A CN 202410493670A CN 118207335 A CN118207335 A CN 118207335A
- Authority
- CN
- China
- Prior art keywords
- chr19
- primer
- detecting
- cyp2b6
- seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000000694 effects Effects 0.000 title claims abstract description 38
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 28
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 17
- 239000003550 marker Substances 0.000 title claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 35
- 238000001514 detection method Methods 0.000 claims abstract description 24
- 102100029152 UDP-glucuronosyltransferase 1A1 Human genes 0.000 claims description 38
- 101710205316 UDP-glucuronosyltransferase 1A1 Proteins 0.000 claims description 38
- 108010020070 Cytochrome P-450 CYP2B6 Proteins 0.000 claims description 29
- 102000009666 Cytochrome P-450 CYP2B6 Human genes 0.000 claims description 29
- 101000799388 Homo sapiens Thiopurine S-methyltransferase Proteins 0.000 claims description 25
- 102100034162 Thiopurine S-methyltransferase Human genes 0.000 claims description 25
- 102100024902 Cytochrome P450 4F2 Human genes 0.000 claims description 24
- 101000909122 Homo sapiens Cytochrome P450 4F2 Proteins 0.000 claims description 24
- 238000011144 upstream manufacturing Methods 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 22
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- 108020004707 nucleic acids Proteins 0.000 claims description 9
- 150000007523 nucleic acids Chemical class 0.000 claims description 9
- 102000039446 nucleic acids Human genes 0.000 claims description 9
- 102100036194 Cytochrome P450 2A6 Human genes 0.000 claims description 7
- 101000875170 Homo sapiens Cytochrome P450 2A6 Proteins 0.000 claims description 7
- 229940034982 antineoplastic agent Drugs 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 238000012163 sequencing technique Methods 0.000 claims description 7
- 102100036661 Acylphosphatase-2 Human genes 0.000 claims description 5
- 102100040999 Catechol O-methyltransferase Human genes 0.000 claims description 5
- 108020002739 Catechol O-methyltransferase Proteins 0.000 claims description 5
- 102100022334 Dihydropyrimidine dehydrogenase [NADP(+)] Human genes 0.000 claims description 5
- 101000884385 Homo sapiens Arylamine N-acetyltransferase 1 Proteins 0.000 claims description 5
- 101000902632 Homo sapiens Dihydropyrimidine dehydrogenase [NADP(+)] Proteins 0.000 claims description 5
- 101001034811 Homo sapiens Eukaryotic translation initiation factor 4 gamma 2 Proteins 0.000 claims description 5
- 101000639975 Homo sapiens Sodium-dependent noradrenaline transporter Proteins 0.000 claims description 5
- 102100033769 Sodium-coupled neutral amino acid transporter 3 Human genes 0.000 claims description 5
- 230000000259 anti-tumor effect Effects 0.000 claims description 5
- 108010001202 Cytochrome P-450 CYP2E1 Proteins 0.000 claims description 4
- 102100024889 Cytochrome P450 2E1 Human genes 0.000 claims description 4
- 101000929554 Homo sapiens Acylphosphatase-2 Proteins 0.000 claims description 3
- 238000003753 real-time PCR Methods 0.000 claims description 3
- 101150007499 Acyp2 gene Proteins 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 101100495914 Arabidopsis thaliana ETL1 gene Proteins 0.000 claims 1
- 229960004316 cisplatin Drugs 0.000 abstract description 16
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 abstract description 16
- 231100000331 toxic Toxicity 0.000 abstract description 15
- 230000002588 toxic effect Effects 0.000 abstract description 15
- 238000002512 chemotherapy Methods 0.000 abstract description 13
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 9
- 201000005202 lung cancer Diseases 0.000 abstract description 9
- 208000020816 lung neoplasm Diseases 0.000 abstract description 9
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 238000003745 diagnosis Methods 0.000 abstract description 2
- 238000010353 genetic engineering Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 21
- 229940079593 drug Drugs 0.000 description 20
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 18
- 239000000523 sample Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- 229910052697 platinum Inorganic materials 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 6
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 6
- 229960004562 carboplatin Drugs 0.000 description 6
- 190000008236 carboplatin Chemical compound 0.000 description 6
- -1 dacatinib Chemical compound 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 238000001959 radiotherapy Methods 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 238000013461 design Methods 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 206010065553 Bone marrow failure Diseases 0.000 description 4
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 4
- 229960002448 dasatinib Drugs 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 3
- 229940044683 chemotherapy drug Drugs 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229960001756 oxaliplatin Drugs 0.000 description 3
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- 102000015790 Asparaginase Human genes 0.000 description 2
- 108010024976 Asparaginase Proteins 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 108091092584 GDNA Proteins 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 2
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 206010033109 Ototoxicity Diseases 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- 108010010056 Terlipressin Proteins 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- 229930183665 actinomycin Natural products 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229960001686 afatinib Drugs 0.000 description 2
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 2
- 229960003982 apatinib Drugs 0.000 description 2
- 229960003272 asparaginase Drugs 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 2
- 229960002707 bendamustine Drugs 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- 229960005061 crizotinib Drugs 0.000 description 2
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 229960003603 decitabine Drugs 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 2
- 229960004783 fotemustine Drugs 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 238000003205 genotyping method Methods 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 230000001861 immunosuppressant effect Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- WPEWQEMJFLWMLV-UHFFFAOYSA-N n-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide Chemical compound C=1C=CN=C(NCC=2C=CN=CC=2)C=1C(=O)NC(C=C1)=CC=C1C1(C#N)CCCC1 WPEWQEMJFLWMLV-UHFFFAOYSA-N 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 229960001346 nilotinib Drugs 0.000 description 2
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 231100000262 ototoxicity Toxicity 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 229960004390 palbociclib Drugs 0.000 description 2
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 2
- 208000035824 paresthesia Diseases 0.000 description 2
- 229960005079 pemetrexed Drugs 0.000 description 2
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229960004432 raltitrexed Drugs 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 229960001796 sunitinib Drugs 0.000 description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 229960001674 tegafur Drugs 0.000 description 2
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 2
- 229960004964 temozolomide Drugs 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- 229960001278 teniposide Drugs 0.000 description 2
- BENFXAYNYRLAIU-QSVFAHTRSA-N terlipressin Chemical compound NCCCC[C@@H](C(=O)NCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)CN)CSSC1 BENFXAYNYRLAIU-QSVFAHTRSA-N 0.000 description 2
- 229960003813 terlipressin Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- 206010043554 thrombocytopenia Diseases 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- 229960004355 vindesine Drugs 0.000 description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 229940127239 5 Hydroxytryptamine receptor antagonist Drugs 0.000 description 1
- 241000143060 Americamysis bahia Species 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 238000007400 DNA extraction Methods 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 241000238557 Decapoda Species 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 101000690100 Homo sapiens U1 small nuclear ribonucleoprotein 70 kDa Proteins 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 108020004711 Nucleic Acid Probes Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010040021 Sensory abnormalities Diseases 0.000 description 1
- 206010059516 Skin toxicity Diseases 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 102100024121 U1 small nuclear ribonucleoprotein 70 kDa Human genes 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 238000011256 aggressive treatment Methods 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000010219 correlation analysis Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 231100000226 haematotoxicity Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- 190000005734 nedaplatin Chemical compound 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000002853 nucleic acid probe Substances 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 238000011518 platinum-based chemotherapy Methods 0.000 description 1
- 238000003793 prenatal diagnosis Methods 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 231100000438 skin toxicity Toxicity 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000001720 vestibular Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Landscapes
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
本发明属于基因工程与肿瘤学技术领域,具体地,涉及一种与抗肿瘤药物引起的副作用相关的SNP标志物及其应用。使用本发明的组合物,能够以最低0.8346的准确度、0.8653的灵敏度以及0.8118的线下面积(AUC值)对肺癌患者使用顺铂化疗是否会发生毒副反应具有预测性,表现了良好的诊断效能。并且其检测稳定、微创、便捷。
Description
技术领域
本发明属于基因工程与肿瘤学技术领域,具体地,涉及一种与抗肿瘤药物引起的副作用相关的SNP标志物及其应用。
背景技术
肺癌是发病率和死亡率均排名靠前的癌种,给人类生命健康带来极大威胁。2022年和2023年连续两年,美国癌症协会估计美国新的癌症病例和死亡人数时,肺癌的发病率在所有癌种中排名第二,死亡率在所有癌种中排名第一。肺癌在不同阶段和亚型中有对应的治疗手段,主要有手术治疗、放射治疗、新辅助化疗、同步放化疗、靶向/免疫治疗等。治疗药物主要有化疗药物、靶向药物和免疫治疗药物。在肺癌的临床实践指南中,铂类药物被作为一线药物使用。铂类药物,尤其是顺铂和卡铂与其它抗肿瘤药物(例如其它种类化疗药物、靶向制剂和免疫制剂)联合使用,相比单药使用提高了疗效。实际上,在近几十年里,铂类药物是治疗多种实体瘤最有希望和最广泛使用的药物之一。铂类药物包括顺铂、卡铂、奈达铂、奥沙利铂等。顺铂和其他铂类衍生物主要通过与DNA结合并形成加合物的方式影响DNA转录和复制来发挥抗癌活性。然而,铂类药物的耐药性和毒副反应限制其临床使用。
铂类化疗的毒副反应涉及多个器官,包括胃肠道、骨髓、神经系统、皮肤、心脏、耳、肝、肾等。化疗导致的胃肠道反应发病表现不一,可以表现为食欲缺乏、恶心、呕吐、腹泻、便秘等,多进行对症治疗。恶心呕吐的发病率最高,常用药物是5-羟色胺受体拮抗剂、地塞米松和奥氮平。化疗导致的骨髓抑制(血液学毒性)属于常见毒副反应,常表现为血细胞下降(白细胞下降、中性粒细胞下降、血小板下降和贫血)。化疗导致的骨髓抑制发生频率高,按严重程度分为Ⅰ、Ⅱ、Ⅲ和Ⅳ级。Ⅲ级和Ⅳ级的骨髓抑制需要积极治疗,严重骨髓抑制无法得到改善的情况下会影响化疗疗效甚至终止化疗。神经毒性主要是周围神经病变(Peripheral Neuropathy,PN),分为急性和慢性。急性PN主要是与冷刺激有关的感觉异常,多发生在四肢远端,持续时间短。慢性PN的特征是双侧对称性感觉异常、感觉迟钝和疼痛,同样多发于四肢远端。部分患者在用药治疗超过一年后仍会出现PN,很可能影响患者的生活质量。皮肤毒性表现为皮肤瘙痒和皮疹。耳毒性表现为双耳永久性听力损失,但也可能出现其他副作用,如耳痛、耳鸣和影响前庭功能(影响平衡)。由于儿童处于生长发育时期,耳毒性更易对其造成影响。肾脏中铂类药物的浓度增加导致肾毒性。其中,肾实质往往比其他组织积聚更多的铂类药物,因为肾脏是顺铂的主要排泄器官。肝毒性主要表现为肝酶(ALT/AST/ALP)或胆红素(TB)的升高。研究发现不同铂类药物导致的毒副反应发生频率不同。顺铂往往导致更严重的恶心、呕吐和肾损伤;卡铂诱导的骨髓毒性发生率较高,尤其容易导致严重的血小板减少。
发明内容
本发明从20万中国人的无创产前诊断测序数据中获得了大批量中国人群代谢酶基因新发现的SNP(均为首次发现),并利用临床样本对其进行了验证,发现部分新发突变具有预测药物敏感性或者毒副反应的功能。
有鉴于此,第一方面,本发明提供一种预测抗肿瘤药物引起的副作用相关的SNP标志物的组合物,包括检测下列SNP标志物中的至少一个的检测试剂:
CYP2A6 chr19:41351944 T>C、CYP2B6 chr19:41510048 A>C、CYP2E1 chr10:135334766 G>A、NAT1 chr8:18056484 A>G、ACYP2 chr2:54531895 A>C、COMT chr22:19956259 A>C、UGT1A1 chr2:234669496 A>C、UGT1A1 chr2:234669582 T>C、UGT1A1 chr2:234681083 T>C、CYP4F2 chr19:16001147 A>G、TPMT chr6:18154786 A>C,或者DPYD chr1:98051517 T>C。
使用本发明的组合物,能够以最低0.8346的准确度、0.8653的灵敏度以及0.8118的线下面积(AUC值)对肺癌患者使用顺铂化疗是否会发生毒副反应具有预测性,表现了良好的诊断效能。并且其检测稳定、微创、便捷。
优选地,所述SNP标志物包括以下组合中的至少一个:
CYP2A6 chr19:41351944 T>C+CYP2B6 chr19:41510048 A>C;
CYP2B6 chr19:41510048 A>C+UGT1A1 chr2:234669496 A>C;
CYP2B6 chr19:41510048 A>C+CYP4F2 chr19:16001147 A>G;
UGT1A1 chr2:234669496 A>C+CYP4F2 chr19:16001147 A>G;
CYP2B6 chr19:41510048 A>C+TPMT chr6:18154786 A>C;
CYP4F2 chr19:16001147 A>G+TPMT chr6:18154786 A>C;
CYP2B6 chr19:41510048 A>C+UGT1A1 chr2:234669496 A>C+CYP4F2 chr19:16001147 A>G;
CYP2B6 chr19:41510048 A>C+UGT1A1 chr2:234669496 A>C+TPMT chr6:18154786 A>C;
CYP2B6 chr19:41510048 A>C+UGT1A1 chr2:234669496 A>C+CYP4F2 chr19:16001147 A>G+TPMT chr6:18154786 A>C;或者
UGT1A1 chr2:234669496 A>C+CYP4F2 chr19:16001147 A>G+TPMT chr6:18154786 A>C。
更优选地,所述SNP标志物包括以下组合中的至少一个:
CYP2B6 chr19:41510048 A>C+UGT1A1 chr2:234669496 A>C;
CYP4F2 chr19:16001147 A>G+TPMT chr6:18154786 A>C;
CYP2B6 chr19:41510048 A>C+UGT1A1 chr2:234669496 A>C+CYP4F2 chr19:16001147 A>G;
CYP2B6 chr19:41510048 A>C+UGT1A1 chr2:234669496 A>C+CYP4F2 chr19:16001147 A>G+TPMT chr6:18154786 A>C;或者
UGT1A1 chr2:234669496 A>C+CYP4F2 chr19:16001147 A>G+TPMT chr6:18154786 A>C。
最优选的,所述所述SNP标志物包括以下组合中的至少一个:
CYP2B6 chr19:41510048 A>C+UGT1A1 chr2:234669496 A>C;
CYP4F2 chr19:16001147 A>G+TPMT chr6:18154786 A>C;或者
CYP2B6 chr19:41510048 A>C+UGT1A1 chr2:234669496 A>C+CYP4F2 chr19:16001147 A>G+TPMT chr6:18154786 A>C。
使用如上的SNP标志物组合能够获得更高的准确度、灵敏度和AUC值。
具体地,所述SNP标志物的信息如下表1所示。
表1
在一些具体的实施方案中,所述SNP标志物通过扩增-测序、芯片、荧光定量PCR的方式测量。
在一些具体的实施方案中,检测试剂包括但不限于核酸引物、测序Tag序列,用于通过扩增-测序检测SNP标志物。
在一些具体的实施方案中,检测试剂包括但不限于芯片,所述芯片是基因芯片,所述基因芯片具有与SNP标志物特异性结合的探针。
在一些具体的实施方案中,检测试剂包括但不限于核酸引物和/或核酸探针,用于通过荧光定量PCR检测SNP标志物。
在一些具体的实施方案中,检测试剂包括但不限于核酸引物和/或单碱基延伸引物,用于通过飞行质谱检测SNP标志物。
在一些具体的实施方案中,检测试剂包括下列中的至少一个:
检测CYP2A6 CHR19:41351944 T>C的如SEQ ID NO.1~3所示的上下游引物和单碱基延伸引物;
检测CYP2B6 chr19:41510048 A>C的如SEQ ID NO.4~6所示的上下游引物和单碱基延伸引物;
检测CYP2E1 chr10:135334766 G>A的如SEQ ID NO.7~9所示的上下游引物和单碱基延伸引物;
检测NAT1 chr8:18056484 A>G的如SEQ ID NO.10~12所示的上下游引物和单碱基延伸引物;
检测ACYP2 chr2:54531895 A>C的如SEQ ID NO.13~15所示的上下游引物和单碱基延伸引物;
检测COMT chr22:19956259 A>C的如SEQ ID NO.16~18所示的上下游引物和单碱基延伸引物;
检测UGT1A1 chr2:234669496 A>C的如SEQ ID NO.19~21所示的上下游引物和单碱基延伸引物;
检测UGT1A1 chr2:234669582 T>C的如SEQ ID NO.22~24所示的上下游引物和单碱基延伸引物;
检测UGT1A1 chr2:234681083 T>C的如SEQ ID NO.25~27所示的上下游引物和单碱基延伸引物;
检测CYP4F2 chr19:16001147 A>G的如SEQ ID NO.28~30所示的上下游引物和单碱基延伸引物;
检测TPMT chr6:18154786 A>C的如SEQ ID NO.31~33所示的上下游引物和单碱基延伸引物;或者
检测DPYD chr1:98051517 T>C的如SEQ ID NO.34~36所示的上下游引物和单碱基延伸引物。
进一步地,所述检测试剂还包括内标引物以及内标探针。
进一步地,上述组合物还可以进一步包括其余的试剂,具体地,例如,各种对样本进行前处理或者预处理所需要的试剂。例如,提取样本核酸的核酸释放剂。
进一步地,所述抗肿瘤药物可以是靶向类药物,例如,阿来替尼、塞瑞替尼、克唑替尼、达沙替尼、伊马替尼、尼洛替尼、达拉非尼、维莫非尼、伊布替尼、泽布替尼、哌柏西利、阿法替尼、达可替尼、厄洛替尼、吉非替尼、埃克替尼、奥希替尼、拉帕替尼、奈拉替尼、芦可替尼、曲美替尼、依维莫司、尼拉帕利、奥拉帕利、阿昔替尼、阿帕替尼、贝伐珠单抗、西妥昔单抗、伊沙佐米、仑伐替尼、尼达尼布、培唑帕尼、帕妥珠单抗、瑞戈非尼、利妥昔单抗、索拉非尼、舒尼替尼、曲妥珠单抗。
进一步地,所述抗肿瘤药物可以是免疫抑制剂,例如,帕博利珠单抗、纳武利尤单抗、卡瑞利珠单抗、替雷利珠单抗、信迪利单抗、特瑞普利单抗、度伐利尤单抗、阿替利珠单抗。
进一步地,所述抗肿瘤药物可以是化疗类药物,例如白消安、卡莫司汀、苯丁酸氮芥、环磷酰胺、达卡巴嗪、福莫司汀、异环磷酰胺、洛莫司汀、塞替派、苯达莫司汀、美法仑、替莫唑胺、阿扎胞苷、卡培他滨、克拉屈滨、阿糖胞苷、地西他滨、氟脲苷、氟达拉滨、氟尿嘧啶、吉西他滨、巯嘌呤、甲氨蝶呤、培美曲塞、雷替曲塞、替加氟、硫鸟嘌呤、博来霉素、放线菌素、柔红霉素、多柔比星、表柔比星、伊达比星、米托蒽醌、多西他赛、依托泊苷、伊立替康、紫杉醇、替尼泊苷、托泊替康、长春碱、长春新碱、长春地辛、长春瑞滨、安吖啶、门冬酰胺酶、卡铂、塞来昔布、顺铂、雌莫司汀、奥沙利铂、培门冬酶、丙卡巴肼、硼替佐米。
优选地,所述抗肿瘤药物为化疗类药物。
更优选地,所述抗肿瘤药物为顺铂。
第二方面,本发明提供了上述组合物在制备用于预测抗肿瘤药物引起的副作用的试剂盒中的用途。
进一步地,所述抗肿瘤药物可以是靶向类药物,例如,阿来替尼、塞瑞替尼、克唑替尼、达沙替尼、伊马替尼、尼洛替尼、达拉非尼、维莫非尼、伊布替尼、泽布替尼、哌柏西利、阿法替尼、达可替尼、厄洛替尼、吉非替尼、埃克替尼、奥希替尼、拉帕替尼、奈拉替尼、芦可替尼、曲美替尼、依维莫司、尼拉帕利、奥拉帕利、阿昔替尼、阿帕替尼、贝伐珠单抗、西妥昔单抗、伊沙佐米、仑伐替尼、尼达尼布、培唑帕尼、帕妥珠单抗、瑞戈非尼、利妥昔单抗、索拉非尼、舒尼替尼、曲妥珠单抗。
进一步地,所述抗肿瘤药物可以是免疫抑制剂,例如,帕博利珠单抗、纳武利尤单抗、卡瑞利珠单抗、替雷利珠单抗、信迪利单抗、特瑞普利单抗、度伐利尤单抗、阿替利珠单抗。
进一步地,所述抗肿瘤药物可以是化疗类药物,例如白消安、卡莫司汀、苯丁酸氮芥、环磷酰胺、达卡巴嗪、福莫司汀、异环磷酰胺、洛莫司汀、塞替派、苯达莫司汀、美法仑、替莫唑胺、阿扎胞苷、卡培他滨、克拉屈滨、阿糖胞苷、地西他滨、氟脲苷、氟达拉滨、氟尿嘧啶、吉西他滨、巯嘌呤、甲氨蝶呤、培美曲塞、雷替曲塞、替加氟、硫鸟嘌呤、博来霉素、放线菌素、柔红霉素、多柔比星、表柔比星、伊达比星、米托蒽醌、多西他赛、依托泊苷、伊立替康、紫杉醇、替尼泊苷、托泊替康、长春碱、长春新碱、长春地辛、长春瑞滨、安吖啶、门冬酰胺酶、卡铂、塞来昔布、顺铂、雌莫司汀、奥沙利铂、培门冬酶、丙卡巴肼、硼替佐米。
优选地,所述抗肿瘤药物为化疗类药物。
更优选地,所述抗肿瘤药物为顺铂。
第三方面,本发明提供了一种预测抗肿瘤药物引起的副作用的试剂盒,包括如上所述的组合物。
进一步地,所述组合物还包括说明书,包括通过组合物预测抗肿瘤药物引起的副作用的说明。
更进一步地,患者携带CYP2A6 chr19:41351944 T>C、CYP2B6 chr19:41510048 A>C、NAT1 chr8:18056484 A>G、ACYP2 chr2:54531895 A>C、UGT1A1 chr2:234669496 A>C、DPYD chr1:98051517 T>C突变(即发生这些突变后)更易发生毒副反应;而患者携带CYP2E1chr10:135334766 G>A、COMT chr22:19956259 A>C、UGT1A1 chr2:234669582 T>C、UGT1A1chr2:234681083 T>C、CYP4F2 chr19:16001147 A>G、TPMT chr6:18154786 A>C突变会对患者有保护作用,更难发生毒副反应,纯和突变的个体预测性能比杂合个体要好。
第四方面,本发明提供一种上述SNP标志物预测抗肿瘤药物引起的副作用的检测方法,包括预测如下步骤:
1)提取或释放待测样本的核酸;
2)使用上述组合物检测所述SNP的基因型;以及
3)根据检测的基因型预测抗肿瘤药物引起的副作用。
本发明提供了一种组合物用于制备用于预测抗肿瘤药物引起的副作用的用途,所述预测包括如下步骤:
1)提取或释放待测样本的核酸;
2)使用上述组合物检测所述SNP的基因型;以及
3)根据检测的基因型预测抗肿瘤药物引起的副作用。
附图说明
图1~12为不同基因型的肺癌患者使用顺铂化疗发生毒副反应和不发生毒副反应的比例;
图13为SNP预测顺铂放疗引起副作用的AUC图。
具体实施方式
下文将结合具体实施方案和实施例,具体阐述本发明,本发明的优点和各种效果将由此更加清楚地呈现。本领域技术人员应理解,这些具体实施方案和实施例是用于说明本发明,而非限制本发明。
实施例1、本发明SNP标志物的获得
2012年至2022年期间,从中南大学湘雅医院招募了所有肺癌患者。所有患者均经组织病理学检查确诊,并接受了至少两个周期的一线铂类(顺铂和卡铂)化疗方案。对每位患者进行体格检查,并详细询问病史。有以下情况的患者将被排除在外:(1)严重并发症;(2)接受过手术;(3)接受过靶向治疗;(4)接受过放疗或其他抗肿瘤治疗。患者的化疗反应根据实体瘤反应评估标准(RECIST)1.1版进行评估。完全应答或部分应答的患者被定义为应答者或药物敏感者。病情稳定或进展的患者被定义为无应答者或耐药性患者。最后,共有1064名患者入组。对于这1064个患者的53个位点进行基因分型,随后进行关联分析。最终有12个位点显著与顺铂化疗的毒副反应有关,具体信息如表1所示。
实施例2、本发明SNP标志物的检测
1.引物设计
(1)SNP序列整理:通过dbSNP数据库,汇总包含待检测SNP位点在内共计200bp的gDNA序列,并以txt格式保存,示例如下:
rs1——CTTCAACTCCTGGGCTCAGGCTCAAGTGATCCTCCGACCTCGGCCTCCTGAAGTGCTGGGATTACAGGCATGAGCCACTGTGTCTGGCCACAATACACAC[T/G]TGACTGTCATTTATAAACTCAAATGACTCAGCTATCAAGATGCCAAATTGGATTTTAGAGAGCCTCCTCCTAGGCACCTGATACTTTCATGCTTGGCTTA
(2)同源序列比对:通过UCSC数据库核实SNP位点所在基因序列在基因组同源性,从而评估分型检测的潜在风险。
(3)引物设计:采用Agena公司的Assay Designer4.0软件进行多重SNP位点的引物设计评估,并根据不同的位点信息酌情调整设计参数,满足最优化标准。
4)引物合成:采用PAGE引物纯化方法,合成每个SNP位点对应的三条引物,分别为两条PCR引物和一条UEP引物,具体如下表2所示。
表2
2.引物配置
(1)PCR引物master mix引物配置:稀释单管PCR master至浓度100μM,加入去离子水混合所有单管PCR master使最终反应PCR master mix浓度为0.5μM。
(2)Extend UEP引物Mix引物配置:稀释单管延伸引物至终浓度500μM,加入引物混合后使得各引物浓度为8μM、10μM、15μM。按照DNA合成产品使用说明计算该条引物分子量、质量数和摩尔数,进而根据所需的浓度计算需加入去离子水的量。将混合好的单管延伸引物根据分子量大小,分别取(小于6300Da)1倍,(6300Da至7200Da)1.2倍,(大于7200Da)1.5倍体积量进行混合待用。
3.DNA质检
采用商业化DNA提取试剂盒,提取血样、组织、细胞、唾液等不同样本类型中的DNA。针对所有DNA样本使用NanoDrop2000仪器进行OD值检测,1.25%琼脂糖凝胶电泳检测,进行质检评估是否符合Massarray SNP分型DNA质量要求,然后将质检合格样本转移至96孔板作为工作液,储存于-20℃备用。
4.MassArray SNP分型步骤
(1)PCR扩增反应
该步骤反应是通过PCR扩增,将含有SNP位点的基因片段从gDNA基因组扩增,产物长度在100-200bp之间。
1)取1.5ml EP管中配置PCR master mix,并振荡低速离心。
2)采用8道或12道移液器,在384孔板的每个加样孔中加入4μl PCR master mix,最后加入1μl模板DNA(20ng/μl)混匀,小心盖上384孔封板膜,并压牢每个孔,防止PCR程序时出现蒸发等现象。1000rpm离心1minute。
3)按照PCR扩增反应程序,将PCR反应板放置于PCR仪上,启动程序。
(2)碱性磷酸酶(SAP)反应
该步骤反应通过碱性磷酸酶处理,将上述PCR反应体系中的dNTP进行磷酸化。
1)在PCR反应结束后,将PCR产物用SAP(shrimp alkaline phosphatase,虾碱性磷酸酶)处理,以去除体系中游离的dNTPs。
2)在新1.5ml EP管中配制碱性磷酸酶处理反应液(SAP mix)。
3)将SAP mix加入384孔PCR反应板,对于每个碱性磷酸酶处理反应孔,反应总体积为7μl,其中PCR产物5μl,SAP mix 2μl。
4)移液完成后,小心盖上384孔封板膜,并压牢每个孔,防止PCR程序时出现蒸发等现象,离心后进行如下反应程序。
5)设置SAP反应程序:37℃20min;85℃5min。并将384孔反应板放置于PCR仪上,启动程序。
(3)单碱基延伸反应:该步骤反应通过UEP引物,在ddNTP体系中进行单碱基延伸反应,形成与待检测SNP基因型互补的单碱基延伸产物。
1)在碱性磷酸酶处理结束后进行单碱基延伸反应,反应体系总体积9μl。
2)在新1.5mlEP管中配制单碱基延伸反应液(EXTEND Mix)。
3)将EXTEND Mix对应加入384孔反应板。
4)移液完成后,小心盖上384孔封板膜,并压牢每个孔,防止PCR程序时出现蒸发等现象,离心后进行延伸反应程序。
(4)树脂纯化
1)在384/6MG Dimple板里均匀填充树脂并放置10分钟使其晾干。
2)在384样本板的每个孔中加16μl水。
3)将384样本板轻轻翻转过来扣在Dimple板上,翻转Dimple与384样本板,然后轻敲使树脂落入样本板的每个孔中。
4)将384样本板放置翻转离心机中室温旋转混匀30分钟。
(5)芯片点样
启动MassARRAY Nanodispenser RS1000点样仪,将树脂纯化后的延伸产物移至384-well SpectroCHIP bioarray上。
(6)质谱检测及数据输出
将点样后的SpectroCHIP芯片使用MALDI-TOF质谱仪分析,检测结果使用TYPER4.0软件获取原始数据及基因分型图,检查数据文件的完整性和正确性,将结果保存入相应存储媒介并递交生物信息室分析。
实施例3、本发明组合物测试样本的检测结果
按照实施例2所述的方法,对样本进行检测,不同基因型的肺癌患者使用顺铂化疗发生毒副反应和不发生毒副反应的比例如图1~12所示。这12个图中红色柱子代表发生毒副反应的患者,蓝色代表未发生毒副反应的患者。利用PLINK软件将每个患者的基因型(是否发生突变)与表型(是否发生毒副反应)进行关联分析,以计算每个位点的显著性(P值)和效应值(OR值)。
本发明具体的SNP预测顺铂放疗引起副作用的结果如下表3所示,其预测的AUC图如图13所示(图中的snp1~12编号分别按照下表的各突变编号)。
表3
实施例4、本发明组合物测试样本的检测结果
进一步地,本发明还尝试了SNP组合物用于预测顺铂放疗引起副作用,其结果如表4所示。
表4
/>
/>
Claims (10)
1.一种预测抗肿瘤药物引起的副作用相关的SNP标志物的组合物,包括检测下列SNP标志物中的至少一个的检测试剂:
CYP2A6 chr19:41351944T>C、CYP2B6 chr19:41510048A>C、CYP2E1chr10:135334766G>A、NAT1 chr8:18056484A>G、ACYP2 chr2:54531895A>C、COMT chr22:19956259A>C、UGT1A1chr2:234669496A>C、UGT1A1chr2:234669582T>C、UGT1A1 chr2:234681083T>C、CYP4F2chr19:16001147A>G、TPMT chr6:18154786A>C,或者DPYD chr1:98051517T>C。
2.根据权利要求1所述的组合物,其特征在于,所述检测试剂包括检测以下SNP标志物组合中的至少一个:
CYP2A6 chr19:41351944T>C+CYP2B6 chr19:41510048A>C;
CYP2B6 chr19:41510048A>C+UGT1A1 chr2:234669496A>C;
CYP2B6 chr19:41510048A>C+CYP4F2 chr19:16001147A>G;
UGT1A1 chr2:234669496A>C+CYP4F2 chr19:16001147A>G;
CYP2B6 chr19:41510048A>C+TPMT chr6:18154786A>C;
CYP4F2 chr19:16001147A>G+TPMT chr6:18154786A>C;
CYP2B6 chr19:41510048A>C+UGT1A1 chr2:234669496A>C+CYP4F2chr19:16001147A>G;
CYP2B6 chr19:41510048A>C+UGT1A1 chr2:234669496A>C+TPMT chr6:18154786A>C;
CYP2B6 chr19:41510048A>C+UGT1A1 chr2:234669496A>C+CYP4F2chr19:16001147A>G+TPMT chr6:18154786A>C;或者
UGT1A1 chr2:234669496A>C+CYP4F2 chr19:16001147A>G+TPMT chr6:18154786A>C。
3.根据权利要求1所述的组合物,其特征在于,所述检测试剂包括检测以下SNP标志物组合中的至少一个:
CYP2B6 chr19:41510048A>C+UGT1A1 chr2:234669496A>C;
CYP4F2 chr19:16001147A>G+TPMT chr6:18154786A>C;
CYP2B6 chr19:41510048A>C+UGT1A1 chr2:234669496A>C+CYP4F2chr19:16001147A>G;
CYP2B6 chr19:41510048A>C+UGT1A1 chr2:234669496A>C+CYP4F2chr19:16001147A>G+TPMT chr6:18154786A>C;或者
UGT1A1 chr2:234669496A>C+CYP4F2 chr19:16001147A>G+TPMT chr6:18154786A>C。
4.根据权利要求1所述的组合物,其特征在于,所述检测试剂包括检测以下SNP标志物组合中的至少一个:
CYP2B6 chr19:41510048A>C+UGT1A1 chr2:234669496A>C;
CYP4F2 chr19:16001147A>G+TPMT chr6:18154786A>C;或者
CYP2B6 chr19:41510048A>C+UGT1A1 chr2:234669496A>C+CYP4F2chr19:16001147A>G+TPMT chr6:18154786A>C。
5.根据权利要求1所述的组合物,其特征在于,所述SNP标志物通过扩增-测序、芯片、荧光定量PCR的方式测量。
6.根据权利要求1所述的组合物,其特征在于,所述检测试剂包括核酸引物、测序Tag序列,或用于通过扩增-测序检测SNP标志物中的至少一种。
7.根据权利要求1所述的组合物,其特征在于,所述检测试剂包括如下中的至少一种:
检测CYP2A6 CHR19:41351944T>C的如SEQ ID NO.1~3所示的上下游引物和单碱基延伸引物;
检测CYP2B6 chr19:41510048A>C的如SEQ ID NO.4~6所示的上下游引物和单碱基延伸引物;
检测CYP2E1 chr10:135334766G>A的如SEQ ID NO.7~9所示的上下游引物和单碱基延伸引物;
检测NAT1 chr8:18056484A>G的如SEQ ID NO.10~12所示的上下游引物和单碱基延伸引物;
检测ACYP2 chr2:54531895A>C的如SEQ ID NO.13~15所示的上下游引物和单碱基延伸引物;
检测COMT chr22:19956259A>C的如SEQ ID NO.16~18所示的上下游引物和单碱基延伸引物;
检测UGT1A1 chr2:234669496A>C的如SEQ ID NO.19~21所示的上下游引物和单碱基延伸引物;
检测UGT1A1 chr2:234669582T>C的如SEQ ID NO.22~24所示的上下游引物和单碱基延伸引物;
检测UGT1A1 chr2:234681083T>C的如SEQ ID NO.25~27所示的上下游引物和单碱基延伸引物;
检测CYP4F2 chr19:16001147A>G的如SEQ ID NO.28~30所示的上下游引物和单碱基延伸引物;
检测TPMT chr6:18154786A>C的如SEQ ID NO.31~33所示的上下游引物和单碱基延伸引物;或者
检测DPYD chr1:98051517T>C的如SEQ ID NO.34~36所示的上下游引物和单碱基延伸引物。
8.根据权利要求1~7中任一项所述的组合物在制备用于预测抗肿瘤药物引起的副作用的试剂盒中的用途。
9.一种预测抗肿瘤药物引起的副作用的试剂盒,包括如权利要求1~7中任一项所述的组合物。
10.一种组合物用于制备用于预测抗肿瘤药物引起的副作用的用途,所述预测包括如下步骤:
1)提取或释放待测样本的核酸;
2)使用如权利要求1~7中任一项所述的组合物检测所述SNP的基因型;以及
3)根据检测的基因型预测抗肿瘤药物引起的副作用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410493670.5A CN118207335A (zh) | 2024-04-23 | 2024-04-23 | 一种与抗肿瘤药物引起的副作用相关的snp标志物及其用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410493670.5A CN118207335A (zh) | 2024-04-23 | 2024-04-23 | 一种与抗肿瘤药物引起的副作用相关的snp标志物及其用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN118207335A true CN118207335A (zh) | 2024-06-18 |
Family
ID=91456260
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410493670.5A Pending CN118207335A (zh) | 2024-04-23 | 2024-04-23 | 一种与抗肿瘤药物引起的副作用相关的snp标志物及其用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN118207335A (zh) |
-
2024
- 2024-04-23 CN CN202410493670.5A patent/CN118207335A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR101540647B1 (ko) | 개인맞춤약물 적용을 위한 한국인 약물유전형 동시다중분석 및 분석 결과를 활용한 약물반응 예측 방법 | |
US20150252440A1 (en) | Methods of Treating Breast Cancer with Anthracycline Therapy | |
CN105874079A (zh) | 用于肺癌的分子诊断测试 | |
CN112210605B (zh) | 用于评估组织免疫反应和诊断预后的dna甲基化检测试剂盒 | |
US20220117927A1 (en) | Methods of treating squamous cell carcinomas with farnesyltransferase inhibitors | |
Ramírez-Pacheco et al. | Mexican childhood acute lymphoblastic leukemia: a pilot study of the MDR1 and MTHFR gene polymorphisms and their associations with clinical outcomes | |
CN108135884A (zh) | 用于治疗aml的药物组合物和治疗有此需要的对象中的aml的方法 | |
CN118207335A (zh) | 一种与抗肿瘤药物引起的副作用相关的snp标志物及其用途 | |
CN116716386A (zh) | 一种用于维生素c缺乏风险评估的检测试剂盒及其应用方法 | |
CN111197076A (zh) | 降高血压药物厄贝沙坦用药指导及基因检测试剂盒 | |
JP2010508859A (ja) | プラチナ配位複合体誘発性の耳毒性を予測する多型性 | |
US20140147516A1 (en) | Polymorphisms predictive of platinum-coordinating compound-induced ototoxicity | |
CN111206083A (zh) | 降高血压药物替米沙坦用药指导基因检测试剂盒 | |
EP4012048A1 (en) | Biomarkers for prognosing response to treatment against pancreatic ductal adenocarnicoma | |
CN111197080A (zh) | 一种用于判别硝苯地平个体化用药型的检测产品 | |
CN115125296B (zh) | 瑞戈非尼药敏标记物及其相关试剂的应用 | |
EP2694681A2 (en) | Pharmacogenetic test for anti-resorptive therapy-associated osteonecrosis of the jaw | |
CN118186073A (zh) | 一种与心血管药物治疗敏感性相关的snp标志物及其用途 | |
US20130011392A1 (en) | Method for assessing the ability of a patient to respond to or be safely treated by a nucleoside analog based-chemotherapy | |
CN111197075A (zh) | 降高血压药物坎地沙坦用药指导及基因检测试剂盒 | |
EP4301879A1 (en) | Methods and systems for diagnosis, classification, and treatment of small cell lung cancer and other high-grade neuroendocrine carcinomas | |
Zhao et al. | A metagenome association study of gut microbiome revealed biomarkers for chemotherapy efficacy in locally advanced and advanced lung cancer | |
WO2023007165A1 (en) | Methods for assessing epigenetic age and cancer risk | |
KR20240017235A (ko) | 시스플라틴에 대하여 내성을 갖는 난소암의 진단을 위한 분석방법 | |
CN115323055A (zh) | 用于中国人群乳腺癌精准诊疗的539基因检测方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination |