Kenji Fujiyoshi1, Tomoya Sudo2,3, Fumihiko Fujita2, Akiko Chino3,4, Kiwamu Akagi3,5, Akinari Takao3,6, Masayoshi Yamada3,7, Kohji Tanakaya3,8, Hideyuki Ishida3,9, Koji Komori3,10, Soichiro Ishihara3,11, Masashi Miguchi3,12, Keiji Hirata3,13, Yasuyuki Miyakura3,14, Toshiaki Ishikawa3,15, Tatsuro Yamaguchi3,6, Naohiro Tomita3,16, Yoichi Ajioka17,18, Kenichi Sugihara15,17. 1. Department of Surgery, Kurume University, 67 Asahi-machi, Kurume, Fukuoka, 830-0037, Japan. fujiyoshi_kenji@med.kurume-u.ac.jp. 2. Department of Surgery, Kurume University, 67 Asahi-machi, Kurume, Fukuoka, 830-0037, Japan. 3. The Committee of Hereditary Colorectal Cancer of the Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan. 4. Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. 5. Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan. 6. Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan. 7. Department of Endoscopy, Gastrointestinal Endoscopy Division, National Cancer Center, Tokyo, Japan. 8. Department of Surgery, Iwakuni Clinical Center, Iwakuni, Japan. 9. Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan. 10. Department of Gastroenterological Surgery, Aichi Cancer Center, Aichi, Japan. 11. Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 12. Department of Gastroenterological Surgery, Hiroshima Prefectural Hospital, Hiroshima, Japan. 13. Department of Surgery I, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan. 14. Department of Surgery, Saitama Medical Center Jichi Medical University, Saitama, Japan. 15. Tokyo Medical and Dental University, Tokyo, Japan. 16. Cancer Treatment Center, Toyonaka Municipal Hospital, Toyonaka, Japan. 17. The Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan. 18. Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
Abstract
BACKGROUND: Complex interactions among endogenous and exogenous factors influence the incidence of colorectal cancer (CRC). Germline mutations in mismatch repair (MMR) genes causing Lynch syndrome (LS) are major endogenous factors. The exogenous factor, alcohol consumption, is potentially associated with CRC incidence among patients with LS. However, insufficient data are available to determine whether alcohol consumption influences the time of the first onset of CRC associated with sex, MMR gene mutations, and anatomical tumor site. METHODS: Among 316 patients with LS identified in a Japanese LS cohort, we included 288 with data on age, sex, proband status, alcohol status, smoking status, tumor location, and MMR gene mutations. Multivariable analysis assessed the association of alcohol consumption with earlier onset of the first CRC. RESULTS: Ever drinkers were associated with higher risk of the first onset of CRC than never drinkers (HR 1.54, 95%CI 1.14-2.07, P = 0.004). The association of the first onset of CRC with alcohol consumption was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations (vs those with pathogenic MSH6, PMS2 and EPCAM mutations), and tumors in the proximal colon cancer (vs distal colon and rectal cancer). CONCLUSIONS: Alcohol consumption was associated with earlier onset of the first CRC in Japanese LS cohort. The association was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations, and tumors located in the proximal colon. Our findings illuminate the mechanism of LS-associated carcinogenesis and serve as a recommendation for discontinuing or ceasing alcohol consumption.
BACKGROUND: Complex interactions among endogenous and exogenous factors influence the incidence of colorectal cancer (CRC). Germline mutations in mismatch repair (MMR) genes causing Lynch syndrome (LS) are major endogenous factors. The exogenous factor, alcohol consumption, is potentially associated with CRC incidence among patients with LS. However, insufficient data are available to determine whether alcohol consumption influences the time of the first onset of CRC associated with sex, MMR gene mutations, and anatomical tumor site. METHODS: Among 316 patients with LS identified in a Japanese LS cohort, we included 288 with data on age, sex, proband status, alcohol status, smoking status, tumor location, and MMR gene mutations. Multivariable analysis assessed the association of alcohol consumption with earlier onset of the first CRC. RESULTS: Ever drinkers were associated with higher risk of the first onset of CRC than never drinkers (HR 1.54, 95%CI 1.14-2.07, P = 0.004). The association of the first onset of CRC with alcohol consumption was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations (vs those with pathogenic MSH6, PMS2 and EPCAM mutations), and tumors in the proximal colon cancer (vs distal colon and rectal cancer). CONCLUSIONS: Alcohol consumption was associated with earlier onset of the first CRC in Japanese LS cohort. The association was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations, and tumors located in the proximal colon. Our findings illuminate the mechanism of LS-associated carcinogenesis and serve as a recommendation for discontinuing or ceasing alcohol consumption.
Authors: Kenji Fujiyoshi; Elspeth A Bruford; Pawel Mroz; Cynthe L Sims; Timothy J O'Leary; Anthony W I Lo; Neng Chen; Nimesh R Patel; Keyur Pravinchandra Patel; Barbara Seliger; Mingyang Song; Federico A Monzon; Alexis B Carter; Margaret L Gulley; Susan M Mockus; Thuy L Phung; Harriet Feilotter; Heather E Williams; Shuji Ogino Journal: Proc Natl Acad Sci U S A Date: 2021-01-19 Impact factor: 12.779