The Landscape of the Heritable Cancer Genome

Abstract

Genome-wide association studies (GWAS) have found hundreds of single nucleotide polymorphisms (SNPs) associated with increased risk of cancer. However, the amount of heritable risk explained by SNPs is limited, leaving most of cancer heritability unexplained. Tumor sequencing projects have shown that causal mutations are enriched in genic regions. We hypothesized that SNPs located in protein coding genes and nearby regulatory regions could explain a significant proportion of the heritable risk of cancer.To perform gene-level heritability analysis, we developed a new method, called Bayesian Gene HERitability Analysis (BAGHERA), to estimate the heritability explained by all genotyped SNPs and by those located in genic regions using GWAS summary statistics. BAGHERA was specifically designed for low heritability traits such as cancer and provides robust heritability estimates under different genetic architectures. BAGHERA-based analysis of 38 cancers reported in the UK Biobank showed that SNPs explain at least 10% of the heritable risk for 14 of them, including late onset malignancies. We then identified 1,146 genes, called cancer heritability genes (CHGs), explaining a significant proportion of cancer heritability. CHGs were involved in hallmark processes controlling the transformation from normal to cancerous cells. Importantly, 60 of them also harbored somatic driver mutations, and 27 are tumor suppressors. Our results suggest that germline and somatic mutation information could be exploited to identify subgroups of individuals at higher risk of cancer in the broader population and could prove useful to establish strategies for early detection and cancer surveillance. SignificanceThis study describes a new statistical method to identify genes associated with cancer heritability in the broader population, creating a map of the heritable cancer genome with gene-level resolution.Research.

A novel tumor mutational burden-based risk model predicts prognosis and correlates with immune infiltration in ovarian cancer

“…TTN, whose mutations are frequently identified in solid tumors, is associated with increased TMB, and patients with mutated TTN have improved outcomes in response to ICBs ( 56 ). We also found that SNP, which could explain a significant proportion of the heritable risk of cancer ( 57 ), is the main variant type in OC. The relationship between some types of SNPs and the occurrence, progression, and treatment of OC has been elucidated, such as the ALDH2∗2 polymorphism (rs671) ( 58 ), the most common SNP in Asia, but further study is still necessary.…”

PIWI-interacting RNAs in cancer: Biogenesis, function, and clinical significance

“…Although most studies have focused on the aberrant expression and function exploration of piRNAs, some studies have still noted the association between piRNAs and genetic variants (72). Single-nucleotide polymorphisms (SNPs) are the most common genetic variations (73). Chu et al found that reference SNP rs11776042 (T > C) in piR-015551 participated in the development of CRC (74).…”

Cancer carrier screening in the general population using whole‐genome sequencing

“…6,7,[11][12][13][14][15][16][17] High-penetrance pathogenic (P) variants are found in 5%-10% of unselected patients with cancer, but most inherited predispositions can be attributed to thousands of alleles common in the population that individually provide only a slightly increased risk of cancer. 10 The best-characterized cancers now have more than 100 genomic regions associated with risk, accounting for more than 15%-20% of familial relative risk. 10 Because cancer driver genes (CDGs) play a key role in cancer development, 18 carriers of germline P/likely pathogenic (LP) variants of these genes will be at risk of cancer.…”

“…10 The best-characterized cancers now have more than 100 genomic regions associated with risk, accounting for more than 15%-20% of familial relative risk. 10 Because cancer driver genes (CDGs) play a key role in cancer development, 18 carriers of germline P/likely pathogenic (LP) variants of these genes will be at risk of cancer. This proposal is supported by the CPGs that are CDGs.…”