Abstract PR005: Features and susceptibility to dietary-induced alkylating damage in colorectal cancer
Authors: Gurjao Carino , Zhong Rong , Haruki Koichiro , Tan Chichun , Li Yvonne , Lee-Six Henry , Reardon Brendan , Ugai Tomotaka , Song Mingyang , Allen Eliezer M. Van , Fuchs Charles S. , Nowak Jonathan A. , Wu Kana , Meyerhardt Jeffrey A. , Giovannucci Edward L. , Townsend Jeffrey P. , Ogino Shuji , Giannakis Marios 
Published: January 2023

Abstract
Introduction: Colorectal cancer (CRC) has several established risk factors, including diet. However, their mutagenic effect has not been observed directly in patients’ tumors and the individuals or ethnic groups who are most susceptible to diet-induced carcinogenesis are yet to be identified. We hypothesized that mutational signature analyses in CRC, coupled with epidemiologic, tumor molecular and patient germline data, can be linked to pre-diagnosis diet and specific germline alterations which can further inform cancer prevention efforts. Methods: We analyzed 900 CRCs with whole-exome sequencing (WES) and prospectively collected pre-diagnosis dietary data from the Nurses’ Health Studies I and II (NHS) and the Health Professionals Follow-up Study (HPFS), as well as 540 The Cancer Genome Atlas (TCGA) tumors and 295 non-Western CRCs from the Pan-Cancer Analysis of Whole Genomes. We additionally examined a sequencing dataset of normal colonic crypts. Following variant calling, mutational signature analyses were performed on cancer specimens using Non-negative Matrix Factorization. We leveraged the WES results to identify all patients that harbored the O-6-Methylguanine-DNA Methyltransferase (MGMT) germline rs16906252 single-nucleotide polymorphism (SNP), which is associated with tumor MGMT promoter hypermethylation and impaired alkylating damage repair. Results: We identified a novel alkylating mutational signature in CRC, which was associated with pre-diagnosis intake of red meats (overall red meat P = 0.017, unprocessed red meat P = 7.8×10-3, processed red meat P = 7.1×10-3, Mann-Whitney test), distal tumor location (P = 1.4×10-4, Mann-Whitney test) and worse CRC-specific survival (P trend = 0.036, multivariable Cox regression). We found a similar mutational signature in normal colonic crypts, suggesting an early oncogenic process. We showed that the alkylating signature’s oncogenicity is mainly mediated by KRAS p.G12D and KRAS p.G13D hotspot mutations. In addition, individuals harboring the MGMT rs16906252 germline SNP had a significant enrichment in tumors with alkylating damage (P = 0.015, Mann-Whitney test) and the effect of the SNP was synergistic with pre-diagnosis red-meat intake (P = 0.0099, Wald Test). Notably, we did not observe the alkylating mutational signature in CRCs from African and East-Asian patients, populations in which the MGMT rs16906252 SNP is largely absent. Conclusions: Through the integration of molecular and epidemiologic data, we identified evidence of red meat-associated alkylating damage in CRCs. This alkylating mutational signature was associated with distal colon location, KRAS oncogenic drivers, and poor CRC-specific survival. In addition, tumor alkylating damage was enriched among individuals harboring the MGMT germline rs16906252 polymorphism, absent in East Asian and African CRC patients and was synergistic with pre-diagnosis red-meat intake. Together, these results have significant implications for dietary-induced carcinogenesis and precision prevention in CRC.
Citation Format: Carino Gurjao, Rong Zhong, Koichiro Haruki, Chichun Tan, Yvonne Li, Henry Lee-Six, Brendan Reardon, Tomotaka Ugai, Mingyang Song, Eliezer M. Van Allen, Charles S. Fuchs, Jonathan A. Nowak, Kana Wu, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Jeffrey P. Townsend, Shuji Ogino, Marios Giannakis. Features and susceptibility to dietary-induced alkylating damage in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR005.