American Association for Cancer Research
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Figure S3 from Discovery and Features of an Alkylating Signature in Colorectal Cancer

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journal contribution
posted on 2023-04-03, 23:27 authored by Carino Gurjao, Rong Zhong, Koichiro Haruki, Yvonne Y. Li, Liam F. Spurr, Henry Lee-Six, Brendan Reardon, Tomotaka Ugai, Xuehong Zhang, Andrew D. Cherniack, Mingyang Song, Eliezer M. Van Allen, Jeffrey A. Meyerhardt, Jonathan A. Nowak, Edward L. Giovannucci, Charles S. Fuchs, Kana Wu, Shuji Ogino, Marios Giannakis

Supplemental Figure 3: Comparison between NHS/ HPFS CRC and COSMIC signatures Cosine similarity heat map between de novo signatures found in NHS/ HPFS (y axis) and COSMIC signatures (x axis). NHS/ HPFS signatures were named after their closest COSMIC mutational process match (in bold)



Cancer Research UK

Nodal Award

Stand Up To Cancer

American Cancer Society Research Scholar Grant

Dana-Farber Harvard Cancer Center

Cancer Center Support

Overseas Research Fellowship



Several risk factors have been established for colorectal cancer, yet their direct mutagenic effects in patients' tumors remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 colorectal cancer cases that had occurred in three U.S.-wide prospective studies with extensive dietary and lifestyle information. We found an alkylating signature that was previously undescribed in colorectal cancer and then showed the existence of a similar mutational process in normal colonic crypts. This alkylating signature is associated with high intakes of processed and unprocessed red meat prior to diagnosis. In addition, this signature was more abundant in the distal colorectum, predicted to target cancer driver mutations KRAS p.G12D, KRAS p.G13D, and PIK3CA p.E545K, and associated with poor survival. Together, these results link for the first time a colorectal mutational signature to a component of diet and further implicate the role of red meat in colorectal cancer initiation and progression. Colorectal cancer has several lifestyle risk factors, but the underlying mutations for most have not been observed directly in tumors. Analysis of 900 colorectal cancers with whole-exome sequencing and epidemiologic annotations revealed an alkylating mutational signature that was associated with red meat consumption and distal tumor location, as well as predicted to target KRAS p.G12D/p.G13D.This article is highlighted in the In This Issue feature, p. 2355

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