Type 2 diabetes mellitus, blood cholesterol, triglyceride and colorectal cancer risk in Lynch syndrome

Aung Ko Win,S. Ghazaleh Dashti,Daniel D. Buchanan,John D. Potter,Noralane M. Lindor,Christophe Rosty,Wing Yan Li ,Jane C. Figueiredo,Finlay Macrae ,John L. Hopper,Polly A. Newcomb,Ingrid Winship ,Robert W. Haile,Stephen N. Thibodeau,Xinwei Hua,Mark Clendenning,Steven Gallinger,Graham Casey,Mark A. Jenkins,Loı̈c Le Marchand ,Sheetal Hardikar,Graham G. Giles

doi:10.1038/s41416-019-0580-9

Abstract

BackgroundType 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population. These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer.MethodsThis study included 2023 (56.4% female) carriers with a mismatch repair gene mutation (737 in MLH1, 928 in MSH2, 230 in MSH6, 106 in PMS2, 22 in EPCAM) recruited by the Colon Cancer Family Registry between 1998 and 2012. Weighted Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between self-reported type 2 diabetes, high cholesterol, triglyceride and colorectal cancer risk.Results Overall, 802 carriers were diagnosed with colorectal cancer at a median age of 42 years. A higher risk of colorectal cancer was observed in those with self-reported type-2 diabetes (HR 1.92; 95% CI, 1.03–3.58) and high cholesterol (HR 1.76; CI 1.23–2.52) compared with those without these conditions. There was no evidence of high triglyceride being associated with colorectal cancer risk.ConclusionFor people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk.

Highlights

Lynch syndrome is caused by a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 or a deletion in EPCAM.[1,2,3,4,5] Lynch syndrome is estimated to be present in one in 279 people in the general population[6] and to cause ~2–5% of all colorectal cancers.[7,8] People with Lynch syndrome are at increased risk of various types of cancers, mainly colorectal cancer
65 who had not completed the interview at baseline recruitment, six with missing age at cancer diagnosis, 13 who did not have data on diabetes mellitus, high cholesterol and high triglyceride and 57 who were censored before age 20 were excluded
In this study of people with Lynch syndrome, we observed a higher risk of colorectal cancer associated with self-reported diagnosis of type 2 diabetes mellitus and high blood cholesterol compared with those without these conditions

Summary

Introduction

Lynch syndrome is caused by a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 or a deletion in EPCAM.[1,2,3,4,5] Lynch syndrome is estimated to be present in one in 279 people in the general population[6] and to cause ~2–5% of all colorectal cancers.[7,8] People with Lynch syndrome are at increased risk of various types of cancers, mainly colorectal cancer. The average cumulative risk of colorectal cancer to age 70 years (95% confidence interval (CI)), for male and female mutation carriers, respectively, has been estimated to be 34% (25–50%) and 36% (25–51%) for MLH1,9 and 47% (36–60%) and 37% (27–50%) for MSH2,9 22% (14–32%) and 10% (5–17%) for MSH6,10 and 7.2% (4.5–13%) and 6.4% (3.8–12%) for PMS2.11. Type 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer. CONCLUSION: For people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk

Methods

Results

Conclusion