Abstract PR01: Fusobacterium nucleatum and mutational landscape of colorectal cancer in whole-exome sequencing analysis

Abstract

Abstract Introduction: Gut microbiota plays an important role in intestinal cancer pathogenesis. An accumulating body of evidence demonstrates the association between Fusobacterium nucleatum (F. nucleatum) and colorectal cancer. However, the underlying mechanistic basis of tumorigenesis remains to be investigated. Method: Within 600 colorectal cancer patients from the Nurses' Health Study and the Health Professionals Follow-up Study, F. nucleatum DNA was measured in formalin-fixed paraffin-embedded specimens using a quantitative PCR assay. We performed a whole-exome sequencing analysis to identify characteristics of somatic mutations in tumors with F. nucleatum compared with tumors without. The hypermutated phenotype was defined as cancer with the mutation rate of more than 12 per mega base. The significantly mutated gene was identified based on the MutSigCV computational tool that accounted for regional heterogeneity in mutation rates across the genome. Results: F. nucleatum was present in 86 colorectal cancer tumors, of which 43 (50%) were tumors with a hypermutated phenotype (hypermutators). Colorectal cancer with F. nucleatum was more likely to be a hypermutator compared with cancer without F. nucleatum (chi-square test, P<0.001). In tumors with the non-hypermutated phenotype, mutation types differed according to F. nucleatum status. Cancer with F. nucleatum tended to have fewer mutations in splice sites compared with cancer without F. nucleatum (chi-square P=0.02). In non-hypermutators with or without F. nucleatum, common recurrently-mutated genes were APC, TP53, KRAS, and PIK3CA among 90 previously identified mutated genes. In 126 hypermutators, the mutation in B2M was observed in 38 cases, of which 12 were F. nucleatum positive. Similarly, the HLA-B mutation was found in 26 hypermutated cases, of which 15 cases were F. nucleatum positive. Discussion: This whole-exome sequencing analysis suggested that colorectal cancer with F. nucleatum tended to exhibit the hypermutated phenotype. The somatic mutational landscape provides mechanistic insight into the link between F. nucleatum and colorectal carcinogenesis. This abstract is also being presented as Poster A17. Citation Format: Reiko Nishihara, Andrew T. Chan, Jasmine Xinmeng Mu, Marios Giannakis, Kosuke Mima, Zhi Rong Qian, Susan Bullman, Aleksandar D. Kostic, Curtis Huttenhower, Wendy Garrett, Edward L. Giovannucci, Matthew Meyerson, Levi A. Garraway, Charles S. Fuchs, Shuji Ogino. Fusobacterium nucleatum and mutational landscape of colorectal cancer in whole-exome sequencing analysis. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr PR01.