Alcohol and colorectal cancer risk subclassified by mutational signatures of DNA mismatch repair deficiency

Aiping Fang; Tomotaka Ugai; Carino Gurjao; Rong Zhong; Zhenhua Liu; Xinyuan Zhang; Peilu Wang; Jonathan Nowak; Molin Wang; Marios Giannakis; Shuji Ogino; Xuehong Zhang; Edward Giovannucci

doi:10.1093/jnci/djae078

Alcohol and colorectal cancer risk subclassified by mutational signatures of DNA mismatch repair deficiency

J Natl Cancer Inst. 2024 Apr 4:djae078. doi: 10.1093/jnci/djae078. Online ahead of print.

Authors

Aiping Fang¹, Tomotaka Ugai^{2

3}, Carino Gurjao^{4

5}, Rong Zhong^{2

6}, Zhenhua Liu^{7

8}, Xinyuan Zhang⁹, Peilu Wang¹⁰, Jonathan Nowak¹¹, Molin Wang^{3

9

12}, Marios Giannakis^{4

5}, Shuji Ogino^{2

3

5

11}, Xuehong Zhang^{1

9}, Edward Giovannucci^{13

3}

Affiliations

¹ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
² Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁷ Department of Nutrition, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA, USA.
⁸ Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.
⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Nutrition and Food Hygiene, School of Public Health, Institute of Nutrition, Fudan University, Shanghai, China.
¹¹ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹² Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹³ Department of ofNutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

PMID: 38574386
DOI: 10.1093/jnci/djae078

Abstract

Background: We examined whether the association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of defective MMR (dMMR)-related tumor mutational signatures (TMSs).

Methods: We used data from 227,916 men and women who participated in the Nurses' Health Study (1980-2016), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2016). Dietary data was collected every 4 years through validated food frequency questionnaires. Relative contributions of two dMMR-related TMSs (c-dMMRa/SBS15 and c-dMMRb/SBS26) were quantified using whole-exome sequencing data in a subset of incident CRC cases. Duplication-method Cox proportional hazards regression models were used to assess the association between alcohol consumption and the risk of CRC subtypes according to different contributions of the TMSs. All statistical tests were 2-sided.

Results: We documented 825 incident CRC cases with available TMS data over 26-36 years of follow-up. The association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of c-dMMRb/SBS26 (P-heterogeneitytrend = 0.02) compared to tumors with lower contributions of this TMS. Compared with nondrinkers, drinkers with ≥15 g/d of alcohol had a high risk of c-dMMRb/SBS26-high CRC [multivariable-adjusted HR: 2.43 (95% CI: 1.55-3.82)], but not c-dMMRb/SBS26-low CRC [0.86 (95% CI: 0.57-1.28)] or c-dMMRb/SBS26-moderate CRC [1.14 (95% CI: 0.76-1.71)]. No significant differential associations were observed for c-dMMRa/SBS15 (P-heterogeneitytrend = 0.41).

Conclusions: High alcohol consumption was associated with an increased incidence of CRC containing higher contributions of c-dMMRb/SBS26, suggesting that alcohol consumption may be involved in colorectal carcinogenesis through the DNA mismatch repair pathway.

Keywords: DNA mismatch repair deficiency; alcohol consumption; colorectal cancer; prospective cohort study; tumor mutational signature.