CN110592213A - 预测新抗原负荷和检测基因组突变的基因panel - Google Patents
预测新抗原负荷和检测基因组突变的基因panel Download PDFInfo
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Abstract
本发明涉及生物技术、DNA突变检测技术和生物信息学领域,尤其涉及一种预测新抗原负荷和检测基因组突变的基因panel。具体而言,本发明涉及一个组合了839个基因的基因panel,结合511个基因融合事件,本发明基因panel能够快速、高效、准确地对新抗原负荷进行预测,还可一次性检测多个位点的DNA突变,以便在癌症免疫治疗过程中根据患者的基因组特征选择最优的个体化治疗药物及方案,此外,本发明基因panel还可用于测量SNV、Indel、CNV、基因融合、MSI、TMB、HLA等多种类型的生物标志物。
Description
技术领域
本发明涉及生物技术、DNA突变检测技术和生物信息学领域,尤其涉及一种预测新抗原负荷和检测基因组突变的基因panel。具体而言,本发明涉及一个组合了839个基因的基因panel,结合511个基因融合事件,用于预测新抗原负荷和检测癌症样本基因组突变。本发明基于DNA突变检测而对新抗原负荷进行定量,以预测个别患者对特定抗癌免疫治疗的反应,还可为癌症患者决定癌症阶段并选择由于基因组突变而定制的抗癌药物。
背景技术
癌症是导致人类死亡的主要原因之一,数据显示,目前全球癌症新发和死亡病例呈持续上升之势,新增病例有近一半出现在亚洲,其中大部分在中国。传统的癌症治疗方法主要包括手术、放疗和化疗,但随着医学科学的进步,免疫治疗、靶向治疗、介入治疗、射频治疗等新治疗方式不断涌现,为癌症患者提供了新的治疗选择。
近年来,癌症的免疫治疗作为一种全新的治疗模式,由于其能够对许多类型的癌症进行有效管控,因此已成为癌症治疗领域的一大研究热点。癌症免疫治疗是通过增强人体本身的免疫系统,清除体内的肿瘤细胞,具体包括过继细胞疗法、免疫检查点阻断剂、非特异性免疫激活剂与癌症疫苗四大类疗法。然而,由于癌症免疫治疗针对非常具体的细胞机制,因此有必要预先对癌症患者个体全面的分子概况(如基因组改变、肿瘤突变负荷或新抗原负荷等)进行准确充分的了解,其中,肿瘤突变负荷(TMB)是在免疫治疗选择里最广为人知的指标之一,不过其评估能力则主要来自TMB中嵌入的抗原负荷。
然而目前为止,在癌症免疫治疗领域,仍缺少针对新抗原负荷的快速、高效、准确的预测方法,而传统的针对少量基因突变的基因测试方法已无法满足多靶点高通量的检测需求。
发明内容
为了更加快速、高效、准确地对新抗原负荷进行预测,以便在癌症免疫治疗过程中根据患者的基因组特征选择最优的个体化治疗药物及方案。本发明提供了一种能够预测新抗原负荷和检测基因组突变的基因panel(基因检测组套),该基因panel是针对839个基因的外离子区域和511个基因对基因DNA设计的,可一次性检测多个位点的DNA突变。此外,该panel还可用于测量SNV、Indel、CNV、基因融合、MSI、TMB、HLA等多种类型的生物标志物。
首先,本发明提供了一种预测新抗原负荷和检测基因组突变的基因panel,该基因panel上包含28,888个用于捕获靶向DNA的靶向DNA探针和511个用于捕获基因与基因DNA融合的融合DNA探针;
其中所述靶向DNA是指人类基因组上下述839个基因的外显子区域:ANO10,AAAS,ABCA1,ABCC3,ABL1,ABL2,ABLIM1,ACIN1,ACOT7,ACSL1,ACTG1,ACTR1B,ACVR1B,ACVR2A,ADAM15,ADAMTS12,ADAR,LPHN2,ADIPOR1,ADNP,ADNP2,AGK,AHCTF1,AHNAK,AHNAK2,AIMP2,AKAP9,AKT1,AKT2,AKT3,ALDH4A1,ALG5,ALK,ALKBH2,ALPK2,AMER1,ANAPC5,ANKLE2,ANKRD12,ANO6,AP4B1,APC,AR,ARAF,AREL1,ARFGEF1,ARFGEF2,ARHGAP17,ARHGAP35,ARHGEF7,ARID1A,ARID2,ARMC5,ASAH2,ASPM,ASXL1,ATM,ATP11B,ATP11C,ATP2A2,ATP6V0D1,ATR,ATRN,ATRX,AXIN1,AXIN2,AXL,B2M,BAP1,BARD1,BAZ1B,BCL2,BCL2L11,BCL6,BCLAF1,BCOR,BCORL1,BICD2,GLTSCR1L,BIRC3,BLM,BLVRA,BMS1,BOD1L1,BRAF,BRAT1,BRCA1,BRCA2,BRIP1,BRWD1,BTAF1,BTK,BTN3A2,C10orf88,C11orf80,C6orf203,CACTIN,CAD,CALR,CAMSAP1,CAMTA2,CAND1,CARD11,CASP5,CASP8,CBL,CCDC168,CCDC43,CCND1,CCND2,CCND3,CCNE1,CD163,CD1C,CD274,CD93,CDC16,CDC25B,CDH1,CDK12,CDK4,CDK6,CDKN2A,CDS1,CEBPA,CEP104,CEP290,CHAF1A,CHD4,CHEK1,CHEK2,CIC,CIRBP,CLCN6,CLK2,CLSTN1,CMKLR1,CNKSR1,CNOT1,RQCD1,COL12A1,COL14A1,COL6A3,COPS2,COX10,CPSF6,CPXM2,CREBBP,CRMP1,CRNKL1,CSDE1,CSF3R,CSNK2A2,CSPG4,CTCF,CTNNB1,CTNND1,CUL1,CUL3,CUX1,CXCR4,CYLD,CYP4B1,DAB2,DCHS1,DCLRE1A,DDR2,DDX27,DDX54,DDX58,DECR1,DENND1A,DHPS,DHX15,DHX29,DHX30,DHX35,DHX38,DHX9,DIAPH3,DIS3,DMBT1,DNAJA2,DNAJC10,DNMT3A,DOCK8,DPP3,DSP,DYRK1A,DYRK1B,DYSF,ECSIT,EDEM1,EDEM2,EDNRB,EFTUD2,EGFR,EIF2AK3,EIF4ENIF1,ELF1,ELF3,ELMO2,ELOVL1,EMC2,EML3,EML4,ENC1,ENPP2,ENTPD4,ENTPD6,EPB41L3,EPCAM,EPHB2,ERBB2,ERBB3,ERBB4,ERCC5,ERMP1,ESR1,ESRP1,ESYT1,ETAA1,ETV6,EXOC2,EZH2,FAHD2A,FAM160A2,FAM208A,FAM83B,FAM8A1,FANCA,FANCC,FANCD2,FANCE,FANCF,FANCG,FANCI,FANCL,FANCM,FARS2,FASTKD3,FASTKD5,FAT1,FBXO4,FBXO42,FBXW7,FERMT3,FES,FGF19,FGF3,FGF4,FGFR1,FGFR2,FGFR3,FGFR4,FLAD1,FLNB,FLT1,FLT3,FMR1,FNDC3A,FNIP1,FOXL2,FOXO1,FOXP1,FPGT,FRY,FSCB,FUBP1,FYN,GABPB1,GANAB,GATA2,GBE1,GBF1,GCDH,GIMAP7,GLI1,GNA11,GNAQ,GNAS,GOLGA3,GOLGB1,GPR137,GPRC5C,GRB14,GRINA,GSDMD,GSK3B,GTF2F1,GTPBP2,GXYLT1,H3F3A,H6PD,HCK,HCST,HEATR1,HEPH,HEXA,HEXDC,HLA-A,HLA-B,HLA-C,HLA-DQB1,HLA-DRB1,HMG20A,HNRNPH1,HNRNPM,HOXB13,HPS1,HRAS,HSD11B1,HSP90AB1,IARS2,IDH1,IDH2,IDS,IFNGR1,IFNGR2,IGF1R,IGF2R,IGSF8,IKBKE,IKZF1,IL7R,IMP4,INHBA,INTS3,INTS5,INTS8,IRF1,IRF3,IRS4,ITGB2,ITPR3,JAK1,JAK2,JAK3,CSRP2BP,KAT6A,KCNMA1,KDM3A,KDR,KEAP1,KIAA0232,KIAA0355,ZSWIM8,KIAA0930,KIAA1279,KIFAP3,KIN,KIT,KLHL36,KMT2C,KRAS,LAIR1,LAMA3,LANCL2,LARP4B,LENG8,LIG4,LILRB4,HNRNPCP5,LONP1,LPIN2,LRBA,LRRC41,LRRIQ3,LTN1,MADD,MAGT1,MAN2B1,MAP2K1,MAP2K2,MAP2K3,MAP2K7,MAPK1,MARK2,MBD1,MBNL1,MCCC1,MCHR2,MCM7,MDM2,MDM4,MECOM,MED13L,MED16,MED25,MEN1,MET,METTL17,MFSD1,MGA,MGAT4B,MINK1,MLH1,MPL,MRE11A,MRPL15,MRPL39,MRPS2,MKL1,MSH2,MSH3,MSH6,MTHFR,MTM1,MTOR,MUT,MUTYH,MXRA5,MYC,MYCN,MYD88,MYO3A,MYO9A,MYOF,NAT10,NBN,NCF4,NCOA6,NDUFAF1,NDUFC2,NF1,NF2,NFE2L2,NFIC,NFIX,NID1,NIPBL,NOC4L,NOL8,NOM1,NOTCH1,NOTCH2,NOTCH3,NOTCH4,NPM1,NR1H2,NR4A2,NRAS,NTHL1,NTRK1,NTRK2,NTRK3,NUDCD1,NUP155,OAS1,OFD1,OR6C68,OXSM,PABPC1,PAK1,PALB2,PAN2,PANK4,PARP14,PARP4,PBRM1,PCCB,PCDH17,PCMTD1,PDCD1LG2,PDGFRA,PDGFRB,PELP1,PEX1,PGAP1,PGAP2,PGM2,PGS1,PHF1,PHF3,PHF6,PHRF1,PIAS4,PIGB,PIGO,PIGQ,PIK3C2G,PIK3CA,PIK3CB,PIK3R1,PKM,PLCB3,PLCG2,PLEC,PLXNA1,PLXND1,PMS1,PMS2,PNPLA8,POLD1,POLE,POLE2,POLR2B,POLR3A,POLR3B,POM121,POT1,PPIL2,PPM1B,SMEK1,PPT1,PRAMEF4,PRDM10,PRDM2,PREX1,PRKACA,PRKAR1A,PRKD2,PRPF31,PRPF6,PSMC4,PSMD2,PSMD9,PSME4,PTCH1,PTEN,PTK2B,PTPN11,PTPN6,PTPRA,PTPRC,PXDN,PXK,QRICH1,QSOX1,QSOX2,R3HDM1,RAB3GAP1,RAC1,RAD50,RAD51,RAD51B,RAD51C,RAD51D,RAD54L,RAD54L2,RAF1,RARA,RB1,RB1CC1,RBM10,RBM12,RBM15,RBMX,RECQL,REL,RET,REV3L,RFC1,RHOA,RHOT2,KIAA1432,RIC8A,RIF1,RNF111,RNF128,RNF145,RNF43,ROBO4,ROS1,RPA1,RPRD2,RPS6KC1,RRP12,RUNX1,SAMD9L,SBNO1,SCAP,SCFD2,SCYL2,SDR16C5,SDSL,SEC23B,SEC23IP,SEC24B,SEC31A,SELP,SEMA4C,SENP1,SEPT6,SERPINB10,SERPINB3,SETBP1,SETD1B,SETD2,SETDB1,SETX,SF1,SF3A3,SF3B1,SH2B1,SIDT2,SIRPA,SLAMF1,SLC12A7,SLC16A4,SLC23A2,SLC25A5,SLC25A6,SLC35F5,SLC39A3,SLC3A2,SLC41A3,SLC5A6,SLC9A6,SLIT2,SMAD3,SMAD4,SMARCA4,SMARCB1,SMC5,SMC6,SMG5,SMO,SNRNP200,SNRPB,SNRPN,SNX19,SNX27,SOCS1,SPAG9,SPOPL,SPRED2,SPTBN1,SPTLC2,SRBD1,SRP72,SRPR,SRSF2,ST3GAL3,STAG2,STAT1,STAT3,STAT5B,STAU2,STEAP3,STK11,STX3,SUCLG2,SUCO,SUN1,SUPT5H,SYCP2,SYNE1,TAB1,TAF1C,TAF1D,TAF3,TAOK3,TAP1,TAP2,TATDN1,TBC1D17,TCEB3,TCF12,TCF20,TCF7L2,TDG,TDRD1,TEAD2,TERT,TET2,TEX10,TFE3,TGFBR2,TGFBRAP1,THAP7,TICAM1,TIMELESS,TIMM44,TIPARP,TJP2,TLE3,TMEM168,SLC35G2,TMEM39B,TMEM57,TMEM63B,TMEM79,TNIP1,TNPO1,TNPO3,TNRC6A,TOP3A,TP53,TP53BP1,TPST2,TRAF7,TRAK1,TRAPPC9,TRIB3,TRIM21,TRIM33,TRIM35,TRMT1,TRMT2A,TRPS1,TRRAP,TSC1,TSC2,TTC7A,TTI1,TTK,TTLL1,TUBGCP2,TUSC3,ZCCHC6,U2AF1,UBA6,UBE4A,UBR2,UFL1,UGGT1,ULK1,UPF2,URGCP,USF1,USP26,USP32,USP38,USP5,USP9X,DIEXF,VCAN,VHL,VIPAS39,VPS13A,VPS13C,VPS33A,C16ORF62,VRK3,WAC,KIAA1033,WDR25,WDR45,WDR6,WDR60,WDR81,WT1,WWC3,XRN2,XYLT2,YAP1,YARS2,YIF1A,YIPF2,YME1L1,ZBTB38,ZC3H18,ZC3HAV1,ZFHX3,ZFP36L2,ZFP37,ZFP82,ZFR,ZHX2,ZMYM3,ZNF148,ZNF223,ZNF318,ZNF609,ZNF777,ZRSR2,BMPR1A,GREM1,KLLN,GALNT12,ABRAXAS1,GEN1,MC1R,MITF,PTCH2,SUFU,PRKACB,RECQL4,CDKN1B,SDHA,SDHB,SDHC,SDHD,SDHAF2,EPAS1,MAX,MDH2,TMEM127,DICER1,FLCN,CDC73,FH,CTR9,REST,TRIM37,GPC3,GPC4,BUB1B,DIS3L2,PAX6,WRN,RHBDF2,VSIG10L,CFTR,SPINK1,PRSS1,EXT1,EXT2,FANCB,XRCC2,MAD2L2,SLX4,UBE2T,SMARCE1,MTAP,PHOX2B,FOXE1,KIF1B,SLC25A11,DLST,ANKRD26,DDX41,PAX5,DDB2,ERCC1,ERCC2,ERCC3,ERCC4,POLH,XPA,XPC,SOS1,RIT1,SBDS,EFL1,DNAJC21,SRP54,SAMD9;
所述基因与基因DNA融合是指下述人类基因对融合产生的DNA片段:ATIC-ALK,BCL2L11-BCL2L11,BCR-ABL1,C2orf44-ALK,CARS-ALK,CCDC6-RET,CD74-NRG1,CD74-ROS1,CLIP1-ROS1,CLTC-ALK,DCTN1-ALK,EML4-ALK,ERC1-RET,ERC1-ROS1,ETV6-NTRK3,EZR-ROS1,FGFR1-TACC1,FGFR1-ZNF703,FGFR3-BAIAP2L1,FGFR3-TACC3,FN1-ALK,GOLGA5-RET,GOPC-ROS1,HIP1-ALK,HLA-A-ROS1,HOOK3-RET,KIAA1598-ROS1,KIF5B-ALK,KIF5B-RET,KLC1-ALK,LMNA-NTRK1,LRIG3-ROS1,MSN-ALK,MYO5A-ROS1,NACC2-NTRK2,NPM1-ALK,NTRK3-ETV6,PCM1-RET,PPFIBP1-ALK,PPFIBP1-ROS1,PRKAR1A-RET,PWWP2A-ROS1,QKI-NTRK2,RANBP2-ALK,SDC4-ROS1,SEC31A-ALK,SLC34A2-ROS1,SQSTM1-ALK,STRN-ALK,TP53-NTRK1,TPM3-ALK,TPM3-NTRK1,TPM3-ROS1,TPM4-ALK,TRIM24-RET,TRIM27-RET,TRIM33-RET,VCL-ALK。
进一步地,本发明基因panel中包含的靶向DNA探针和融合DNA探针为核苷酸寡聚物,并分别与靶向DNA或DNA融合互补。
优选地,上述靶向DNA探针和融合DNA探针的探头大小为75~200个核苷酸,平均大小为120个核苷酸。
进一步地,本发明基因panel其检测基因组突变是通过对比靶向DNA序列和野生型参考DNA序列来进行的,所述基因组突变是指与野生型参考DNA序列相比,靶向DNA序列发生了核苷酸变化,包括核苷酸变异(SNV)、核苷酸插入、核苷酸删除、拷贝数变异(CNV)、核苷酸易位、基因与基因融合。
进一步地,本发明还涉及上述基因panel检测到的基因组突变在下列肿瘤生物学行为中的用途:预测新抗原负荷、测算肿瘤突变负荷、预测免疫治疗响应能力、选择靶向治疗药物或治疗方案、检查微卫星不稳定(MSI)状态、判别目的基因的类型、评估个体肿瘤易感性。
另外,本发明基因panel通过对新抗原负荷、基因组突变、目的基因类型的检测,可为癌症患者提供个体化免疫治疗药物及免疫治疗方案。
进一步地,本发明还涉及上述基因panel在检测下列生物标志物中的应用:SNV、Indel、CNV、基因融合、MSI、TMB、HLA。
本发明还涉及上述基因panel在肿瘤医学中的应用。
本发明还涉及上述基因panel在生物医学中的应用。
本发明基因panel能够快速、高效、准确地对新抗原负荷进行预测,还可一次性检测多个位点的DNA突变,以便在癌症免疫治疗过程中根据患者的基因组特征选择最优的个体化治疗药物及方案,还可用于测量SNV、Indel、CNV、基因融合、MSI、TMB、HLA等多种类型的生物标志物。
附图说明
图1:本发明基因panel工作流程图。
图2:显示NGS文库数量和质量的Tapestation数据。
图3:使用基因panel捕获的目标DNA的数量和质量的Tapestation数据。
图4:与参考基因组比对的序列读数的实例,以检测从靶标捕获的DNA读取的突变序列。
具体实施方式
以下通过特定的具体实例详细描述本发明的实施方式,但是以下具体实施方式本质上仅是示例,本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。
为使本领域技术人员了解本发明的特点及效果,以下就说明书及权利要求书中提及的术语及用语进行一般性的说明及定义。除非另有指明,本发明中使用的所有技术和科学术语与本领域技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外,根据本领域技术人员对现有技术的掌握及本发明的记载,还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明。
在本发明中,若无特别说明,所有的设备和原料均可从商业途径得到或是本行业常用的。下述实施例中的方法,如无特别说明,均为本领域的常规方法。
实施例:
1、下一代测序的文库准备
(1)利用Qiagen DNeasy试剂盒或QIAamp游离核酸提取试剂盒(Qiagen)从样本(如癌组织、血液或其他类型的癌症活检组织)中提取基因组DNA;
(2)使用Qubit 3.0荧光定量仪(Thermofisher)和Tapestation系统(Agilent)检查提取基因组DNA的数量和质量;
(3)输入10-100ng基因组DNA并使用NeoCura NGS文库制备试剂盒来进行NGS文库制备;
(4)使用Qubit 3.0荧光定量仪和Tapestation系统检查NGS文库的数量和质量(参见图2)。
2、使用基因panel捕获目标DNA
(1)使用100-500ng的库来做目标捕获;
(2)在65℃条件下与基因panel探针杂交4-16小时;
(3)使用DynabeadsTM M-270链霉抗生物素蛋白磁珠对捕获的目标DNA进行分离,然后纯化;
(4)使用PCR方法扩增纯靶向DNA;
(5)使用Qubit 3.0荧光定量仪和Tapestation系统检查捕获库的数量和质量(参见图3)。
3、下一代测序和突变检测
(1)捕获的库将提交到Illumina NGS计算机(如Illumina HiSeqX)以生成原始序列数据文件(即FASTQ文件);
(2)采集的序列读取被馈送到内部序列QC管道以生成序列QC报告;
(3)通过质量控制的序列读取与参考基因组对齐(hg38基因组);
(4)使用内部变体调用算法检测对齐序列读取的DNA突变(参见图4);
(5)检测到的突变结果汇总到下表1中。
表1基因突变检测结果
基因 | 突变 | 参考VAF(%) | 检测VAF(%) |
AKT1 | E17K | 5.0 | 3.6 |
BRAF | V600E | 18.2 | 14.5 |
BRCA2 | K1691Nfs*15 | 5.6 | 9.7 |
EGFR | A767-V769dup | 5.6 | 7.5 |
EGFR | E746-A750del | 5.3 | 1.5 |
EGFR | G719S | 5.3 | 4.4 |
FLT3 | P986Afs*27 | 5.6 | 10.7 |
GNA11 | Q209L | 5.6 | 5.3 |
KRAS | G13D | 5.6 | 4.2 |
MET | L238Yfs*25 | 2.5 | 4.2 |
NOTCH1 | P668S | 5.0 | 3.2 |
PIK3CA | E545K | 5.6 | 4.2 |
PIK3CA | H1047R | 16.7 | 16.1 |
以上对本发明优选的具体实施方式和实施例作了详细说明,但是本发明并不限于上述实施方式和实施例,在本领域技术人员所具备的知识范围内,还可以在不脱离本发明构思的前提下作出各种变化。
Claims (9)
1.一种预测新抗原负荷和检测基因组突变的基因panel,其特征在于:所述基因panel上包含28,888个用于捕获靶向DNA的靶向DNA探针和511个用于捕获基因与基因DNA融合的融合DNA探针;
其中所述靶向DNA是指人类基因组上下述839个基因的外显子区域:ANO10,AAAS,ABCA1,ABCC3,ABL1,ABL2,ABLIM1,ACIN1,ACOT7,ACSL1,ACTG1,ACTR1B,ACVR1B,ACVR2A,ADAM15,ADAMTS12,ADAR,LPHN2,ADIPOR1,ADNP,ADNP2,AGK,AHCTF1,AHNAK,AHNAK2,AIMP2,AKAP9,AKT1,AKT2,AKT3,ALDH4A1,ALG5,ALK,ALKBH2,ALPK2,AMER1,ANAPC5,ANKLE2,ANKRD12,ANO6,AP4B1,APC,AR,ARAF,AREL1,ARFGEF1,ARFGEF2,ARHGAP17,ARHGAP35,ARHGEF7,ARID1A,ARID2,ARMC5,ASAH2,ASPM,ASXL1,ATM,ATP11B,ATP11C,ATP2A2,ATP6V0D1,ATR,ATRN,ATRX,AXIN1,AXIN2,AXL,B2M,BAP1,BARD1,BAZ1B,BCL2,BCL2L11,BCL6,BCLAF1,BCOR,BCORL1,BICD2,GLTSCR1L,BIRC3,BLM,BLVRA,BMS1,BOD1L1,BRAF,BRAT1,BRCA1,BRCA2,BRIP1,BRWD1,BTAF1,BTK,BTN3A2,C10orf88,C11orf80,C6orf203,CACTIN,CAD,CALR,CAMSAP1,CAMTA2,CAND1,CARD11,CASP5,CASP8,CBL,CCDC168,CCDC43,CCND1,CCND2,CCND3,CCNE1,CD163,CD1C,CD274,CD93,CDC16,CDC25B,CDH1,CDK12,CDK4,CDK6,CDKN2A,CDS1,CEBPA,CEP104,CEP290,CHAF1A,CHD4,CHEK1,CHEK2,CIC,CIRBP,CLCN6,CLK2,CLSTN1,CMKLR1,CNKSR1,CNOT1,RQCD1,COL12A1,COL14A1,COL6A3,COPS2,COX10,CPSF6,CPXM2,CREBBP,CRMP1,CRNKL1,CSDE1,CSF3R,CSNK2A2,CSPG4,CTCF,CTNNB1,CTNND1,CUL1,CUL3,CUX1,CXCR4,CYLD,CYP4B1,DAB2,DCHS1,DCLRE1A,DDR2,DDX27,DDX54,DDX58,DECR1,DENND1A,DHPS,DHX15,DHX29,DHX30,DHX35,DHX38,DHX9,DIAPH3,DIS3,DMBT1,DNAJA2,DNAJC10,DNMT3A,DOCK8,DPP3,DSP,DYRK1A,DYRK1B,DYSF,ECSIT,EDEM1,EDEM2,EDNRB,EFTUD2,EGFR,EIF2AK3,EIF4ENIF1,ELF1,ELF3,ELMO2,ELOVL1,EMC2,EML3,EML4,ENC1,ENPP2,ENTPD4,ENTPD6,EPB41L3,EPCAM,EPHB2,ERBB2,ERBB3,ERBB4,ERCC5,ERMP1,ESR1,ESRP1,ESYT1,ETAA1,ETV6,EXOC2,EZH2,FAHD2A,FAM160A2,FAM208A,FAM83B,FAM8A1,FANCA,FANCC,FANCD2,FANCE,FANCF,FANCG,FANCI,FANCL,FANCM,FARS2,FASTKD3,FASTKD5,FAT1,FBXO4,FBXO42,FBXW7,FERMT3,FES,FGF19,FGF3,FGF4,FGFR1,FGFR2,FGFR3,FGFR4,FLAD1,FLNB,FLT1,FLT3,FMR1,FNDC3A,FNIP1,FOXL2,FOXO1,FOXP1,FPGT,FRY,FSCB,FUBP1,FYN,GABPB1,GANAB,GATA2,GBE1,GBF1,GCDH,GIMAP7,GLI1,GNA11,GNAQ,GNAS,GOLGA3,GOLGB1,GPR137,GPRC5C,GRB14,GRINA,GSDMD,GSK3B,GTF2F1,GTPBP2,GXYLT1,H3F3A,H6PD,HCK,HCST,HEATR1,HEPH,HEXA,HEXDC,HLA-A,HLA-B,HLA-C,HLA-DQB1,HLA-DRB1,HMG20A,HNRNPH1,HNRNPM,HOXB13,HPS1,HRAS,HSD11B1,HSP90AB1,IARS2,IDH1,IDH2,IDS,IFNGR1,IFNGR2,IGF1R,IGF2R,IGSF8,IKBKE,IKZF1,IL7R,IMP4,INHBA,INTS3,INTS5,INTS8,IRF1,IRF3,IRS4,ITGB2,ITPR3,JAK1,JAK2,JAK3,CSRP2BP,KAT6A,KCNMA1,KDM3A,KDR,KEAP1,KIAA0232,KIAA0355,ZSWIM8,KIAA0930,KIAA1279,KIFAP3,KIN,KIT,KLHL36,KMT2C,KRAS,LAIR1,LAMA3,LANCL2,LARP4B,LENG8,LIG4,LILRB4,HNRNPCP5,LONP1,LPIN2,LRBA,LRRC41,LRRIQ3,LTN1,MADD,MAGT1,MAN2B1,MAP2K1,MAP2K2,MAP2K3,MAP2K7,MAPK1,MARK2,MBD1,MBNL1,MCCC1,MCHR2,MCM7,MDM2,MDM4,MECOM,MED13L,MED16,MED25,MEN1,MET,METTL17,MFSD1,MGA,MGAT4B,MINK1,MLH1,MPL,MRE11A,MRPL15,MRPL39,MRPS2,MKL1,MSH2,MSH3,MSH6,MTHFR,MTM1,MTOR,MUT,MUTYH,MXRA5,MYC,MYCN,MYD88,MYO3A,MYO9A,MYOF,NAT10,NBN,NCF4,NCOA6,NDUFAF1,NDUFC2,NF1,NF2,NFE2L2,NFIC,NFIX,NID1,NIPBL,NOC4L,NOL8,NOM1,NOTCH1,NOTCH2,NOTCH3,NOTCH4,NPM1,NR1H2,NR4A2,NRAS,NTHL1,NTRK1,NTRK2,NTRK3,NUDCD1,NUP155,OAS1,OFD1,OR6C68,OXSM,PABPC1,PAK1,PALB2,PAN2,PANK4,PARP14,PARP4,PBRM1,PCCB,PCDH17,PCMTD1,PDCD1LG2,PDGFRA,PDGFRB,PELP1,PEX1,PGAP1,PGAP2,PGM2,PGS1,PHF1,PHF3,PHF6,PHRF1,PIAS4,PIGB,PIGO,PIGQ,PIK3C2G,PIK3CA,PIK3CB,PIK3R1,PKM,PLCB3,PLCG2,PLEC,PLXNA1,PLXND1,PMS1,PMS2,PNPLA8,POLD1,POLE,POLE2,POLR2B,POLR3A,POLR3B,POM121,POT1,PPIL2,PPM1B,SMEK1,PPT1,PRAMEF4,PRDM10,PRDM2,PREX1,PRKACA,PRKAR1A,PRKD2,PRPF31,PRPF6,PSMC4,PSMD2,PSMD9,PSME4,PTCH1,PTEN,PTK2B,PTPN11,PTPN6,PTPRA,PTPRC,PXDN,PXK,QRICH1,QSOX1,QSOX2,R3HDM1,RAB3GAP1,RAC1,RAD50,RAD51,RAD51B,RAD51C,RAD51D,RAD54L,RAD54L2,RAF1,RARA,RB1,RB1CC1,RBM10,RBM12,RBM15,RBMX,RECQL,REL,RET,REV3L,RFC1,RHOA,RHOT2,KIAA1432,RIC8A,RIF1,RNF111,RNF128,RNF145,RNF43,ROBO4,ROS1,RPA1,RPRD2,RPS6KC1,RRP12,RUNX1,SAMD9L,SBNO1,SCAP,SCFD2,SCYL2,SDR16C5,SDSL,SEC23B,SEC23IP,SEC24B,SEC31A,SELP,SEMA4C,SENP1,SEPT6,SERPINB10,SERPINB3,SETBP1,SETD1B,SETD2,SETDB1,SETX,SF1,SF3A3,SF3B1,SH2B1,SIDT2,SIRPA,SLAMF1,SLC12A7,SLC16A4,SLC23A2,SLC25A5,SLC25A6,SLC35F5,SLC39A3,SLC3A2,SLC41A3,SLC5A6,SLC9A6,SLIT2,SMAD3,SMAD4,SMARCA4,SMARCB1,SMC5,SMC6,SMG5,SMO,SNRNP200,SNRPB,SNRPN,SNX19,SNX27,SOCS1,SPAG9,SPOPL,SPRED2,SPTBN1,SPTLC2,SRBD1,SRP72,SRPR,SRSF2,ST3GAL3,STAG2,STAT1,STAT3,STAT5B,STAU2,STEAP3,STK11,STX3,SUCLG2,SUCO,SUN1,SUPT5H,SYCP2,SYNE1,TAB1,TAF1C,TAF1D,TAF3,TAOK3,TAP1,TAP2,TATDN1,TBC1D17,TCEB3,TCF12,TCF20,TCF7L2,TDG,TDRD1,TEAD2,TERT,TET2,TEX10,TFE3,TGFBR2,TGFBRAP1,THAP7,TICAM1,TIMELESS,TIMM44,TIPARP,TJP2,TLE3,TMEM168,SLC35G2,TMEM39B,TMEM57,TMEM63B,TMEM79,TNIP1,TNPO1,TNPO3,TNRC6A,TOP3A,TP53,TP53BP1,TPST2,TRAF7,TRAK1,TRAPPC9,TRIB3,TRIM21,TRIM33,TRIM35,TRMT1,TRMT2A,TRPS1,TRRAP,TSC1,TSC2,TTC7A,TTI1,TTK,TTLL1,TUBGCP2,TUSC3,ZCCHC6,U2AF1,UBA6,UBE4A,UBR2,UFL1,UGGT1,ULK1,UPF2,URGCP,USF1,USP26,USP32,USP38,USP5,USP9X,DIEXF,VCAN,VHL,VIPAS39,VPS13A,VPS13C,VPS33A,C16ORF62,VRK3,WAC,KIAA1033,WDR25,WDR45,WDR6,WDR60,WDR81,WT1,WWC3,XRN2,XYLT2,YAP1,YARS2,YIF1A,YIPF2,YME1L1,ZBTB38,ZC3H18,ZC3HAV1,ZFHX3,ZFP36L2,ZFP37,ZFP82,ZFR,ZHX2,ZMYM3,ZNF148,ZNF223,ZNF318,ZNF609,ZNF777,ZRSR2,BMPR1A,GREM1,KLLN,GALNT12,ABRAXAS1,GEN1,MC1R,MITF,PTCH2,SUFU,PRKACB,RECQL4,CDKN1B,SDHA,SDHB,SDHC,SDHD,SDHAF2,EPAS1,MAX,MDH2,TMEM127,DICER1,FLCN,CDC73,FH,CTR9,REST,TRIM37,GPC3,GPC4,BUB1B,DIS3L2,PAX6,WRN,RHBDF2,VSIG10L,CFTR,SPINK1,PRSS1,EXT1,EXT2,FANCB,XRCC2,MAD2L2,SLX4,UBE2T,SMARCE1,MTAP,PHOX2B,FOXE1,KIF1B,SLC25A11,DLST,ANKRD26,DDX41,PAX5,DDB2,ERCC1,ERCC2,ERCC3,ERCC4,POLH,XPA,XPC,SOS1,RIT1,SBDS,EFL1,DNAJC21,SRP54,SAMD9;
所述基因与基因DNA融合是指下述人类基因对融合产生的DNA片段:ATIC-ALK,BCL2L11-BCL2L11,BCR-ABL1,C2orf44-ALK,CARS-ALK,CCDC6-RET,CD74-NRG1,CD74-ROS1,CLIP1-ROS1,CLTC-ALK,DCTN1-ALK,EML4-ALK,ERC1-RET,ERC1-ROS1,ETV6-NTRK3,EZR-ROS1,FGFR1-TACC1,FGFR1-ZNF703,FGFR3-BAIAP2L1,FGFR3-TACC3,FN1-ALK,GOLGA5-RET,GOPC-ROS1,HIP1-ALK,HLA-A-ROS1,HOOK3-RET,KIAA1598-ROS1,KIF5B-ALK,KIF5B-RET,KLC1-ALK,LMNA-NTRK1,LRIG3-ROS1,MSN-ALK,MYO5A-ROS1,NACC2-NTRK2,NPM1-ALK,NTRK3-ETV6,PCM1-RET,PPFIBP1-ALK,PPFIBP1-ROS1,PRKAR1A-RET,PWWP2A-ROS1,QKI-NTRK2,RANBP2-ALK,SDC4-ROS1,SEC31A-ALK,SLC34A2-ROS1,SQSTM1-ALK,STRN-ALK,TP53-NTRK1,TPM3-ALK,TPM3-NTRK1,TPM3-ROS1,TPM4-ALK,TRIM24-RET,TRIM27-RET,TRIM33-RET,VCL-ALK。
2.如权利要求1所述的基因panel,其中所述靶向DNA探针和融合DNA探针为核苷酸寡聚物,并分别与靶向DNA或DNA融合互补。
3.如权利要求2所述的基因panel,其中所述靶向DNA探针和融合DNA探针的探头大小为75~200个核苷酸,平均大小为120个核苷酸。
4.如权利要求1所述的基因panel,其检测基因组突变是通过对比靶向DNA序列和野生型参考DNA序列来进行的,所述基因组突变是指与野生型参考DNA序列相比,靶向DNA序列发生了核苷酸变化,包括核苷酸变异、核苷酸插入、核苷酸删除、拷贝数变异、核苷酸易位、基因与基因融合。
5.如权利要求4所述的基因panel,检测到的基因组突变在下列肿瘤生物学行为中的用途:预测新抗原负荷、测算肿瘤突变负荷、预测免疫治疗响应能力、选择靶向治疗药物或治疗方案、检查微卫星不稳定状态、判别目的基因的类型、评估个体肿瘤易感性。
6.如权利要求1所述的基因panel,所述基因panel通过对新抗原负荷、基因组突变、目的基因类型的检测,为癌症患者提供个体化免疫治疗药物及免疫治疗方案。
7.如权利要求1所述的基因panel在检测下列生物标志物中的应用:SNV、Indel、CNV、基因融合、MSI、TMB、HLA。
8.如权利要求1-7任一项所述的基因panel在肿瘤医学中的应用。
9.如权利要求1-7任一项所述的基因panel在生物医学中的应用。
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