The pan-cancer landscape of prognostic germline variants in 10,582 patients

Abstract

Background: While clinical factors such as age, grade, stage, and histological subtype provide physicians with information about patient prognosis, genomic data can further improve these predictions. Previous studies have shown that germline variants in known cancer driver genes are predictive of patient outcome, but no study has systematically analyzed multiple cancers in an unbiased way to identify genetic loci that can improve patient outcome predictions made using clinical factors. Methods: We analyzed sequencing data from the over 10,000 cancer patients available through The Cancer Genome Atlas to identify germline variants associated with patient outcome using multivariate Cox regression models. Results: We identified 79 prognostic germline variants in individual cancers and 112 prognostic germline variants in groups of cancers. The germline variants identified in individual cancers provide additional predictive power about patient outcomes beyond clinical information currently in use and may therefore augment clinical decisions based on expected tumor aggressiveness. Molecularly, at least 12 of the germline variants are likely associated with patient outcome through perturbation of protein structure and at least five through association with gene expression differences. Almost half of these germline variants are in previously reported tumor suppressors, oncogenes or cancer driver genes with the other half pointing to genomic loci that should be further investigated for their roles in cancers. Conclusions: Germline variants are predictive of outcome in cancer patients and specific germline variants can improve patient outcome predictions beyond predictions made using clinical factors alone. The germline variants also implicate new means by which known oncogenes, tumor suppressor genes, and driver genes are perturbed in cancer and suggest roles in cancer for other genes that have not been extensively studied in oncology. Further studies in other cancer cohorts are necessary to confirm that germline variation is associated with outcome in cancer patients as this is a proof-of-principle study.

Germline variants predictive of tumor mutational burden and immune checkpoint inhibitor efficacy

“…We next sought to characterize the somatic events associated with GVITMB. Several studies have suggested that germline variants influence somatic events ( Carter et al., 2017 ; Chatrath et al., 2019 , 2020 ; Chirita-Emandi et al., 2020 ). We found that patients with GVITMB in mismatch repair genes exhibited enrichment of mutational signatures associated with mismatch repair gene dysfunction, suggesting exome-wide evidence of the dysfunction of these genes ( Table 4 ).…”

“…Although patients with pathogenic germline variants are often screened more aggressively for cancer, clinical guidelines for these patients have only changed in a few circumstances ( Le et al., 2017 ; Lindor et al., 2006 ). We had previously identified common germline variants associated with differences in patient outcome across a multitude of cancers, suggesting that germline variation contributes not only to cancer risk but also to tumor progression ( Chatrath et al., 2019 , 2020 ). In this study, we have identified pathogenic germline variants associated with TMB.…”

“…We have reported that germline variants affect tumor progression across a large spectrum of cancers through the analysis of common germline variants with a minor allele frequency greater than 5% in the general population ( Chatrath et al., 2019 , 2020 ). In this study, we analyze rare pathogenic germline variants to identify germline variants associated with increased tumor mutational burden (GVITMB) to test whether these germline variants increase the likelihood of a patient responding to immune checkpoint inhibitors ( Keenan et al., 2019 ; Liu et al., 2019 ; Miao et al., 2018 ).…”

Crohn's disease-associated ATG16L1 T300A genotype is associated with improved survival in gastric cancer

“…Although most variants demonstrate a modest increase in risk [ 5 ], the combined effects of multiple SNPs are potentially useful in population-based cancer risk stratification and prevention programs [ 13 , 14 ]. Likewise, GWAS studies have also identified SNPs associated with response to chemotherapy [ 15 ], treatment-related toxicity [ 16 ], and clinical outcomes in cancer patients [ [17] , [18] , [19] ]. Therefore, identifying SNPs and other genetic alterations that correlate with clinical outcome may provide novel insight into the pathobiology and management of cancer.…”

Inferred Ancestral Origin of Cancer Cell Lines Associates with Differential Drug Response

“…On the other hand, germline variants have been known to influence the somatic mutational landscape of cancer tumours by changing the structures of genes and amino acid sequences, affecting the distribution of somatic mutations and causing global enrichment of mutations [ 8 ]. So far, many studies have revealed the direct effect of germline variants or their interaction with somatic mutations in predicting the outcome of patient treatments or sensitivity of cancer cell lines in high-throughput drug screens (HTSs) [ 9 , 10 , 11 ].…”