Abstract and Introduction
Abstract
Introduction Lynch syndrome is known to cause an increased risk of malignancies, including bowel and endometrial cancers. However, the risk of breast cancer associated with mutations in the mismatch repair (MMR) genes that cause Lynch syndrome is still unclear.
Materials and methods This study assesses the cumulative risk of breast cancer in 106 MLH1 and 118 MSH2 families. Families were referred on the basis of clinical criteria. Pedigree information was obtained, and tumour immunohistochemistry and microsatellite testing performed. Appropriate patients underwent sequencing and multiple ligation dependent probe amplification of all relevant exons of the MMR genes. Kaplan–Meier analysis of cumulative lifetime risk of breast cancer was made combining proven mutation carriers and their first-degree female relatives.
Results After allocation of mutation status, the cumulative risk of breast cancer to 70 years in MLH1 carriers was 18.6% (95% CI 11.3 to 25.9)). This is significantly higher than the cumulative risk for MSH2 which was 11.2% (95% CI 1.4 to 21.0) to age 70 years (p=0.014). The UK population risk is 7.5%–8% at the age of 70 years. Prospective analysis identified six breast cancers in 1120 years of follow-up with an OR of 3.41 (95% CI 1.53 to 7.59).
Discussions Female MLH1 carriers would appear to be at moderate risk of breast cancer and should be considered for breast screening at ages earlier than national screening programmes.
Introduction
Lynch syndrome (previously hereditary non-polyposis colorectal cancer) is an inherited cancer predisposition syndrome caused by inactivation mutations of the DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2, and mutations in EPCAM (leading to impaired DNA repair through inactivation of MSH2). It is associated with an increased lifetime risk of colorectal cancers and a spectrum of extracolonic tumours, including endometrial, ovarian, upper urothelial, biliary, brain and small bowel malignancy. The inclusion of breast cancer within this syndrome is controversial.
Early studies on the risk of breast cancer in Lynch syndrome were based on individuals ascertained by differing clinical criteria (including, in some cases on the basis of prior breast cancer). Subsequent to the mapping of the MMR loci in 1993, several studies have examined the relative risk in MLH1 and MSH2 carriers. Scott et al found that breast cancer incidence was over-represented in MLH1 carriers, but not in MSH2 carriers (17 MLH1 families and 15 MSH2 families). This was contradicted by Vasen et al who did not find an increased risk for 187 MLH1 mutation carriers and 141 MSH2 mutation carriers, although the mean age at breast cancer diagnosis in carriers was young at 46 years. More recently, a prospective study by Win et al found an increased risk of breast cancer in 446 unaffected mutation carriers (MLH1 and MSH2 combined) over a median follow-up of 5 years. Win et al also demonstrated that women carrying MMR gene mutations were at increased risk of breast cancer following endometrial or colorectal cancer. Women with MSH2 mutations were more likely to develop breast cancer following colorectal cancer, but there was no significant difference between the genes following endometrial cancer, although the number of cancers was small.
Engel et al also reported an increased risk of breast cancer in 2118 mutation carriers (806 MLH1, 1004 MSH2 and 308 MSH6) but there was no significant difference in risk between genes.
Additional evidence for the role of MMR mutation in the pathogenesis of breast cancers is provided by the presence of microsatellite instability (MSI) in breast tumour tissue from subjects with both MLH1 and MSH2 mutations. MSI is present in only a fraction of the sporadic breast cancers studied, and the occurrence of instability in breast tumours of MMR mutation carriers implies a distinct molecular genetic basis for their origin.
The Regional Genetics Service at St Mary's Hospital covers the population of the North West England. Two hundred and twenty-four Lynch syndrome families with proven pathological mutations in the MMR genes are known to this service. We report the cumulative lifetime risk of breast cancer for mutation carriers within this cohort.