A genome-wide cross-cancer meta-analysis highlights the shared genetic links of five solid cancers

Abstract

Breast, ovarian, prostate, lung, and head/neck cancers are five solid cancers with complex interrelationships. However, the shared genetic factors of the five cancers were often revealed either by the combination of individual genome-wide association study (GWAS) approach or by the fixed-effect model-based meta-analysis approach with practically impossible assumptions. Here, we presented a random-effect model-based cross-cancer meta-analysis framework for identifying the genetic variants jointly influencing the five solid cancers. A comprehensive genetic correlation analysis (genome-wide, partitioned, and local) approach was performed by using GWAS summary statistics of the five cancers, and we observed three cancer pairs with significant genetic correlation: breast–ovarian cancer (rg = 0.221, p = 0.0003), breast–lung cancer (rg = 0.234, p = 7.6 × 10−6), and lung–head/neck cancer (rg = 0.652, p = 0.010). Furthermore, a random-effect model-based cross-trait meta-analysis was conducted for each significant cancer pair, and we found 27 shared genetic loci between breast and ovarian cancers, 18 loci between breast and lung cancers, and three loci between lung and head/neck cancers. Functional analysis indicates that the shared genes are enriched in human T-cell leukemia virus 1 infection (HTLV-1) and antigen processing and presentation (APP) pathways. Our study investigates the shared genetic links across five solid cancers and will help to reveal their potential molecular mechanisms.