Genetic Determinants Of The Somatic Mutational Processes In Cancers Reveal Potential Driver Genes Of Cancer Evolution

During tumorigenesis and progression,cancer cells undergo different somatic mutational processes which often generate different combinations of mutation types resulting in tumor heterogeneity and drug resistance.Therefore,the studies of cancer somatic mutation processes are beneficial to uncover the underlying mechanism of canceration and discover potential therapeutic targets.Many studies reported that somatic mutations of certain genes are associated with somatic mutation processes,but the causality is not clear.Obviously,the hereditary germline variants occur before the somatic mutational processes.If the germline variants affect the somatic signatures,then the germline variants must be the pathogenic factor.Therefore,the germline variants are beneficial to define the causality between genes and somatic processes.By combining the germline variants and somatic mutations,we aimed to identify the driver genes and risk loci of somatic mutational processes and explain tumorigenesis and somatic evolution.Firstly,we analyzed the somatic mutational signatures in 302 paired whole-exome sequencing data of Esophageal Squamous Cell Carcinomas(ESCC)in a Chinese population.We found ZNF750 and CDC27,of which the somatic statuses and the genetic burdens consistently associated with the same somatic mutational signatures in ESCC:ZNF750 was known as driver gene of ESCC and associated with the APOBEC mutational process;CDC27 was the new driver gene of ESCC and associated with the NpCpG and the APOBEC mutational processes(FDR<0.1).Secondly,we systematically analyzed 3,566 samples of 13 cancer types and found 2,330 candidate driver genes that are associated with the specific somatic processes.The candidate driver genes significantly enriched for dependency genes which enhance cancer cell viability(P=1.03×10-12),and also 16.7%of COSMIC genes(P=9.08×10-3,OR=1.28)and 21.1%of cancer risk genes(P=7.90×10-3,OR=1.69),such as ATM,BRCA1,CHECK.102 of the candidate driver genes were the clinical accelerator drug targets,such as MMP2,ALK;and 343 genes of which certain variants have significant prognostic efficacy,such as IL32 and CTSO.We found that 60%of the significantly enriched pathways were metabolic pathways.By instrumental variable analysis,we found the 491 of 2,330 genes' expression was associated with certain somatic processes,which improved the accuracy of identifying driver genes.In addition,we identified 1,244 mutation signature quantitative trait loci(msQTL;P<1×10-6)of which 90.8%were the known eQTL.We also found that the 12 proxy SNPs(r2>0.5)of rs1321311 which is the CO AD risk site of Caucasians significantly affects the tobacco mutation process in COAD(P<1×10-6).By instrumental variable analysis,we found that 66 of 1,244 msQTL may affect somatic signatures through affecting the expression of cisgenes,and the cis-genes expression are associated with survival outcome of at least one cancer type.Based on the evidence of germline and somatic variants,we reveal potential determinants of somatic mutation processes,identify the specific drive mutations and oncogenes,and provide a lot of targets for the diagnosis,treatment,prognosis,and the new ideas for cancer research.