Quantifying the Genetic Correlation between Multiple Cancer Types

Abstract

Many cancers share specific genetic risk factors including both rare high-penetrance mutations and common single nucleotide polymorphisms (SNPs) identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies. In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry. We also estimated genetic correlations between cancers and 14 non-cancer diseases and traits. After adjusting for 15 pair-wise genetic correlation tests between cancers, we found significant (p<0.003) genetic correlations between pancreatic and colorectal cancer (rg=0.55, p=0.003), lung and colorectal cancer (rg=0.31, p=0.001). We also found suggestive genetic correlations between lung and breast cancer (rg=0.27, p=0.009), and colorectal and breast cancer (rg=0.22, p=0.01). In contrast, we found no evidence that prostate cancer shared an appreciable proportion of heritability with other cancers. After adjusting for 84 tests studying genetic correlations between cancer types and other traits (Bonferroni-corrected p-value: 0.0006), only the genetic correlation between lung cancer and smoking remained significant (rg=0.41, p=1.03x10-6). We also observed nominally significant genetic correlations between body mass index (BMI) and all cancers except ovarian cancer. Our results highlight novel genetic correlations and lend support to previous observational studies that have observed links between cancers and risk factors.

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

“…Several were also similar to array-based heritability estimates from consortia comprised of multiple studies. [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).…”

“…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.…”

“…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).…”

Assessing a causal relationship between circulating lipids and breast cancer risk: Mendelian randomization study

“…An ideal approach would consider the effects of body mass index (BMI) and age at menarche, known risk factors for breast cancer that are correlated with lipids. [13][14][15][16][17][18][19] In what follows, we apply the causal inference framework of MR to determine if genetically elevated lipid traits modify breast cancer susceptibility, independent of one another and of BMI and age at menarche. We take advantage of a recent GWAS for lipid levels performed in up to 215,551 individuals of European ancestry 20 to provide power for our causal inference analyses.…”