Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study

We carried out a hospital-based case-control study in a Caucasian Portuguese population (287 cases and 547 controls) to estimate the susceptibility to non-familial breast cancer associated with some polymorphisms in mismatch repair genes (MSH3, MSH4, MSH6, MLH1, MLH3, PMS1 and MUTYH).Using unconditional logistic regression we found that MLH3 (L844P, G>A) polymorphism GA (Leu/Pro) and AA (Pro/Pro) genotypes were associated with a decreased risk: OR = 0.65 (0.45-0.95) (p = 0.03) and OR = 0.62 (0.41-0.94) (p = 0.03), respectively.Analysis of two-way SNP interaction effects on breast cancer revealed two potential associations to breast cancer susceptibility: MSH3 Ala1045Thr/MSH6 Gly39Glu - AA/TC [OR = 0.43 (0.21-0.83), p = 0.01] associated with a decreased risk; and MSH4 Ala97Thr/MLH3 Leu844Pro - AG/AA [OR = 2.35 (1.23-4.49), p = 0.01], GG/AA [OR = 2.11 (1.12-3,98), p = 0.02], and GG/AG [adjusted OR = 1.88 (1.12-3.15), p = 0.02] all associated with an increased risk for breast cancer.It is possible that some of these common variants in MMR genes contribute significantly to breast cancer susceptibility. However, further studies with a large sample size will be needed to support our results.Breast cancer is the first leading cause of cancer mortality in women in the United States and Europe and current estimates suggest that one in eight American women will be diagnosed with breast carcinoma [1]. Various genetic and environmental factors have been established as causes of breast cancer, which is a genetically heterogeneous disease [2-4].Several studies have identified two major susceptibility genes in breast cancer: BRCA1 and BRCA2 [5]. These genes have an important role in genome maintenance, in cell-cycle control and in DNA repair in the control of homologous recombination [6,7]. Analysis in families with high risk of breast cancer showed that individuals with point mutations in these genes have a 40-80% of probability to develop breast cancer. However, mutations in the