Lynch syndrome: the influence of environmental factors on extracolonic cancer risk in hMLH1 c.C1528T mutation carriers and their mutation-negative sisters

Abstract

Lynch Syndrome (LS) is a cancer susceptibility syndrome caused mostly by mutations in the mismatch repair genes, hMLH1, hMSH2 and hMSH6. Mutation carriers are at risk of colorectal and endometrial cancer and, less frequently, cancer of the ovaries, stomach, small bowel, hepatobiliary tract, ureter, renal pelvis and brain. The influence of environmental factors on extracolonic cancer risk in LS patients has not been investigated thus far. The aim of this study was to investigate some of these factors in South African females carrying the hMLH1 c.C1528T mutation and their mutation-negative relatives. Data were collected from 87 mutation-positive females and 121 mutation-negative female relatives regarding age, cancer history, hormonal contraceptive use, parity, duration of breast feeding, height, weight and age at first birth, last birth, menarche and menopause. Influence of these factors on cancer risk was analysed by mixed-effects generalised linear models. Extracolonic cancer occurred in 14% (12/ 87) of mutation-positive females versus 7% (8/121) of mutation-negative females, (P = 0.0279, adjusted for age and relatedness between women). Breast cancer was the most common extracolonic cancer. An association was found for oral contraceptive use and extracolonic cancer risk in mutation-negative females only. No association was found for any of the other risk factors investigated, when adjusted for age. This might be due to the scarcity of extracolonic cancers in our data. Future knowledge on the influence of additional environmental factors on cancer risk in LS females can lead to evidence-based lifestyle advice for mutation carriers, thereby complementing the prevention strategies available today. In addition, it can contribute to an integrated model of cancer aetiology. Therefore, this study should be taken as a thrust for further research.

Female Hormonal Factors and the Risk of Endometrial Cancer in Lynch Syndrome

“…Similarly, we did not observe statistically significant association between endometrial cancer risk and age at first and last live birth in Lynch syndrome, which is in line with some 13, 35 but not all studies 35, 36 conducted in the general population. 37 The lack of an observed association between endometrial cancer risk and PMH use in this study could be attributed to lack of statistical power (only 2.8% reported use of estrogen-only and 4.3% reported use of combined estrogen and progesterone for at least one year). Additional unmeasured confounding or information bias could also account for this finding.…”

Correlation Between Body Mass Index and Prevalence of Hereditary Nonpolyposis Colorectal Cancer in Korean Patients With Endometrial Cancer

“…Clinicopathological characteristics of the patients with HNPCC related to endometrial cancer HNPCC in Koreans are similar to those in Americans and Europeans,9,12 such as diabetes, age of menarche, menopause status, parity, histology, FIGO stage, and tumor grade.…”

Clinical significance of mismatch repair gene expression in sporadic colorectal cancer

“…A number of tumor-related events are involved in this process, including oncogene activation, tumor suppressor gene inactivation, mismatch repair (MMR) gene mutations and gene promoter hypermethylation ( 1 , 2 ). Since the identification of MMR genes, studies have investigated the association between the aberrant expression of MMR genes and hereditary nonpolyposis colorectal cancer (HNPCC) or sporadic colorectal cancer ( 3 – 5 ). A number of studies have found that aberrant MMR gene expression plays an important role in the occurrence of colorectal cancer ( 6 , 7 ).…”