Genetic and microbial determinants of azoxymethane-induced colorectal tumor susceptibility in Collaborative Cross mice and their implication in human cancer
Dan Li,
Chenhan Zhong,
Mengyuan Yang,
Li He,
Hang Chang,
Ning Zhu,
Susan E Celniker,
David W Threadgill,
Antoine M Snijders,
Jian-Hua Mao,
Ying Yuan
Affiliations
Dan Li
Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ZJ, China
Chenhan Zhong
Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ZJ, China
Mengyuan Yang
Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ZJ, China
Li He
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Hang Chang
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Ning Zhu
Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ZJ, China
Susan E Celniker
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
David W Threadgill
Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, TX, USA
Antoine M Snijders
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Jian-Hua Mao
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Ying Yuan
Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ZJ, China
ABSTRACTThe 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. We identified 4417 CTS-associated single nucleotide polymorphisms (SNPs) containing 334 genes that were transcriptionally altered in human colorectal cancers (CRCs) and consistently clustered independent human CRC cohorts into two subgroups with different prognosis. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that accurately predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs associated with abundances of these genera. Mediation analysis revealed GM as mediators partially exerting the effect of SNP 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. Our findings provide potential novel targets for personalized CRC prevention and treatment.
