Genetic and microbial determinants of azoxymethane-induced colorectal tumor susceptibility in Collaborative Cross mice and their implication in human cancer

Abstract

Abstract Background The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse population model to identify genetic and microbial determinants of Azoxymethane-induced CTS. Results We identified 4417 CTS-associated SNPs containing 936 known human genes, 334 of which were found to be transcriptionally altered in human CRCs. Transcriptional expression of 334 CTS genes clustered human CRCs into two subgroups with prognostic impact in independent cohorts. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs significantly associated with the abundances of at least 5 of 16 genera. Mediation analysis revealed GM as mediators exerting genetic effects on CTS, whereby Ruminococcus, Akkermansia, Allobaculum, Bacteroides, Sutterella, and Bifidobacterium mediate the effect of UNC3869242 within Duox2 on CTS. Intestine cell-specific depletion of Duox2 altered GM composition and contribution of Duox2 depletion to CTS was significantly influenced by GM. Conclusions This study identifies genetic and microbial determinants of azoxymethane-induced CTS, shows critical importance of interaction between genetics and microbiome in CTS, and provides potential novel targets for personalized CRC prevention and treatment.