Combination of 247 Genome-Wide Association Studies Reveals High Cancer Risk as a Result of Evolutionary Adaptation

Analysis of GLOBOCAN-2012 data shows clearly here that cancer incidence worldwide is highly related with low average annual temperatures and extreme low temperatures. This applies for all cancers together or separately formany frequent or rare cancer types (all cancers P = 9.49 x 10(-18)). Supporting fact is that Inuit people, living at extreme low temperatures, have the highest cancer rates today. Hypothesizing an evolutionary explanation, 240 cancer genome-wide association studies, and seven genome-wide association studies for cold and high-altitude adaptation were combined. A list of 1,377 cancer-associated genes was created to initially investigate whether cold selected genes are enriched with cancerassociated genes. Among Native Americans, Inuit and Eskimos, the highest association was observed for Native Americans (P = 6.7 x 10(-5)). An overall or a meta-analysis approach confirmed further this result. Similar approach for three populations living at extreme high altitude, revealed high association for Andeans-Tibetans (P = 1.3 x 10(-11)). Overall analysis or a meta-analysis was also significant. A separate analysis showed special selection for tumor suppressor genes. These results can be viewed along with those of previous functional studies that showed that reduced apoptosis potential due to specific p53 variants (the most important tumor suppressor gene) is beneficial in high-altitude and cold environments. In conclusion, this study shows that genetic variants selected for adaptation at extreme environmental conditions can increase cancer risk later on age. This is in accordance with antagonistic pleiotropy hypothesis.