Abstract 1590: Robust evolutionary conservation and pair-wise co-mapping of polygenic colon and lung cancer susceptibility loci

Abstract Comparing chromosomal locations of statistically significant colon and lung cancer susceptibility loci detected by linkage in mouse and rat and by GWAS in humans revealed conservation of position of most of them in spite of the 70 million years of separate rodent and primate evolution. 1. When projected onto their corresponding homologous positions in the mouse genome, 79% of human, and rat loci as well as mouse loci mapped together in 31 distinct short clusters, which indicate presence of at least 31 evolutionary conserved colon/lung cancer susceptibility genes or gene pairs. 2. These co-localizations indicate also an evolutionary conservation of the hierarchy of strength of colon and lung cancer susceptibility genes. Generally, both in linkage and in GWAS studies a subset of genes with the largest effect will reach the significance threshold early, while many other genes will remain beneath it and may reach significance only in later studies, especially meta-analyzes. As we analyzed only significant genes, the co-mapping of their majority into the 31 clusters has been possible only if the subsets of genes with the largest effects are very similar in all three species. 3. In addition, the majority of colon and lung cancer susceptibility QTLs formed linked pairs. Consequently, all 31 clusters contained both colon and lung cancer susceptibility QTLs. 4. This pair-wise genomic location of colon and lung cancer QTLs seemed to be associated with their similar quantitative effects on tumorigenesis, as tests of congenic mouse strains each carrying 87% of BALB/c genome and differing from each other in a small subset of colon cancer QTLs revealed that the two strains with very high colon cancer susceptibility and the two strains with very low colon cancer susceptibility exhibited concordantly very high and very low susceptibility to lung cancer, respectively. 5. It has to be established whether the co-mapping of colon and lung cancer susceptibility QTLs and concordant magnitude of their effect on colon and lung cancer indicate that a single gene or two paired organ-specific genes control development of colon and lung cancer. 6. In summary, genetic location and relative strength of polygenic colon and lung cancer susceptibility QTLs have been surprisingly conserved during separate evolution of rodents and primates. These QTLs exhibit frequent pairwise linkage of colon and lung cancer susceptibility loci and directionally correlated effects on both cancers. 7. The presented findings indicate that a majority of colon and lung cancer susceptibility QTLs are robust genetic and biological entities, whose individual functions in colon and lung carcinogenesis may be effectively studied. As the combined mortality of colon and lung cancers exceeds that of combined five other major cancer sources of deaths, their study can have a significant translational impact. Citation Format: Lei Quan, Alan Hutson, Peter Demant. Robust evolutionary conservation and pair-wise co-mapping of polygenic colon and lung cancer susceptibility loci [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1590.