Shared heritability and functional enrichment across six solid cancers

Abstract

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg=0.57, p=4.6×10−8), breast and ovarian cancer (rg=0.24, p=7×10−5), breast and lung cancer (rg=0.18, p=1.5×10−6) and breast and colorectal cancer (rg=0.15, p=1.1×10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Pan-Cancer Study Detects Novel Genetic Risk Variants and Shared Genetic Basis in Two Large Cohorts

“…[4][5][6] For example, our estimate for testicular cancer closely matches the previous family-based estimate of heritability (h 2 =0.25; 95% CI: 0.15-0.37), 3 as well as a previous estimate of array-based heritability (h 2 =0.30; 95% CI: 0.08-0.51). 4 For lung cancer, our estimated heritability of h 2 =0.15 (95% CI: 0.10-0.20) approaches the twin-based estimate of h 2 =0.18 (95% CI: 0.00-0.42), 2 exceeds the array-based estimate from a study using the same methodology (h 2 =0.08; 95% CI: 0.05-0.10), 6 and is comparable to an earlier array-based estimate using individual-level data (h 2 =0.21; 95% CI: 0.14-0.27). 4 For rectal (h 2 =0.11; 95% CI: 0.07-0.16) and bladder (h 2 =0.08; 95% CI: 0.04-0.12) cancers, our heritability estimates are close to those from twin/family studies -h 2 =0.14 (95%CI: 0.00-0.50) 2 and h 2 =0.07 (95% CI: 0.02-0.11), 3 respectively.…”

“…1 Efforts toward cancer prevention, screening, and treatment are thus imperative, but they require a more comprehensive understanding of the underpinnings of carcinogenesis than we currently possess. While studies of twins, 2 families, 3 and unrelated populations [4][5][6] have demonstrated substantial heritability and familial clustering for many cancers, the extent to which genetic variation is unique versus shared across different types of cancer remains unclear.…”

“…In addition to individual variants, recent studies have evaluated genome-wide genetic correlations between pairs of cancer types. [4][5][6] One evaluated 13 cancer types and found shared heritability between kidney and testicular cancers, diffuse large B-cell lymphoma (DLBCL) and osteosarcoma, DLBCL and chronic lymphocytic leukemia (CLL), and bladder and lung cancers. 4 Another study of six cancer types found correlations between colorectal cancer and both lung and pancreatic cancers.…”

“…5 In an updated analysis with increased sample size, the same group identified correlations of breast cancer with colorectal, lung, and ovarian cancers and of lung cancer with colorectal and head/neck cancers. 6 While these studies provide compelling evidence for shared heritability across cancers, they lack data on several cancer types (e.g., cervix, melanoma, and thyroid).…”

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

“…Significant genetic correlations with FEV1 and FVC were observed for lung cancer overall, in smokers, and for tumors with squamous cell histology, but not adenocarcinoma. Jiang et al 25 reported a similar magnitude of genetic correlation with FEV1/FVC, but did not observe an association with FVC, and did not assess FEV1. Differences in our results may be attributable to their use of GWAS summary statistics for pulmonary phenotypes from the interim UK Biobank release.…”