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

Abstract

BackgroundMMR is responsible for the repair of base-base mismatches and insertion/deletion loops. Besides this, MMR is also associated with an anti-recombination function, suppressing homologous recombination. Losses of heterozygosity and/or microsatellite instability have been detected in a large number of skin samples from breast cancer patients, suggesting a potential role of MMR in breast cancer susceptibility.MethodsWe 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).ResultsUsing 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.ConclusionIt 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.

Correlation of MSH3 polymorphisms with response and survival in advanced non-small cell lung cancer patients treated with first-line platinum-based chemotherapy

“…Hirata et al (2008) found that the G/G or G/A genotype of the MSH3 rs26279 polymorphism might be a risk factor for sporadic prostate cancer. Moreover, the genetic variant of the MSH3 rs26279/MSH6 Gly39Glu -AA/ TC was associated with a decreased risk for breast cancer (Conde et al, 2009). Although the function of this polymorphism is unknown, our data also revealed that NSCLC patients with the G/G genotype had a decreased response to platinum-based treatments.…”

“…MMR genes play an important role in removing DDP-DNA adducts and mutation in MMR genes may lead to a decreased response to platinum-based chemotherapy (Conde-Pérezprina et al, 2012). The MSH3 gene is located on chromosome 5q11-13 and was first described in 1989 (Hirata et al, 2008); somatic mutation of MSH3 occurs frequently in MMR-deficient cancers, such as colon carcinoma (Takahashi et al, 2011;Park et al, 2013), lung cancer, breast cancer (Conde et al, 2009) and oral squamous cell carcinoma (Mondal et al, 2013). The association of MSH3 gene polymorphisms in ovarian cancer has also been reported, which suggests that MSH3 polymorphism may be a risk factor for ovarian cancer (Song et al, 2006).…”

MutYH mutation carriers have increased breast cancer risk

“…7 It is known that mutations in mismatch-repair genes increase susceptibility to cancer in organs other than the colon, but former data published regarding a possible association between MutYH mutations and breast cancer risk are conflicting. [8][9][10][11][12][13][14] We studied the prevalence of the 2 commonly described founder mutations in MutYH, a glycine-to-aspartic acid substitution at codon 396 (G396D) and a tyrosine-to-cysteine substitution at codon 179 (Y179C), in a case-control study of breast cancer that was restricted to Sephardi Jews in whom we noted a high prevalence of these mutations (unpublished results).…”

MLH1 Polymorphisms and Cancer risk: a Meta-analysis Based on 33 Case-control Studies

“…Most studies indicated that the genotypes distribution in the controls was consistent with Hardy-Weinberg equilibrium except for six studies for -93G>A (Park et al, 2004;Beiner et al, 2006;An et al, 2008;Harley et al, 2008;Scott et al, 2008;Shih et al, 2010) and four studies for I219V (Listgarten et al, 2004;An et al, 2008;Conde et al, 2009;Nejda et al, 2009). Diverse genotyping methods were used, including polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), TaqMan, and matrix-assisted laser desorption ionization time-of-flight (Chip-based MALDI-TOF) mass spectrometry.…”

“…There are 20 case-control studies concerning -93G>A polymorphism (Ito et al, 1999;Deng et al, 2003;Park et al, 2004;Chen et al, 2005;Lee et al, 2005;Beiner et al, 2006;Song et al, 2006;Raptis et al, 2007;An et al, 2008;Harley et al, 2008;Koessler et al, 2008;Scott et al, 2008;Tulupova et al, 2008;Campbell et al, 2009;Shi et al, 2010;Shih et al, 2010;van Roon et al, 2010;Lacey et al, 2011;Lo et al, 2011;Whiffin et al, 2011) and 18 studies for I219V (Mathonnet et al, 2003;Listgarten et al, 2004;Lee et al, 2005;Mei et al, 2006;Song et al, 2006;Raptis et al, 2007;An et al, 2008;Capella et al, 2008;Smith et al, 2008;Campbell et al, 2009;Conde et al, 2009;Joshi et al, 2009;Nejda et al, 2009;Tanaka et al, 2009;Langeberg et al, 2010;Picelli et al, 2010 polymorphisms are summarized in Table 1. Most studies indicated that the genotypes distribution in the controls was consistent with Hardy-Weinberg equilibrium except for six studies for -93G>A (Park et al, 2004;Beiner et al, 2006;An...…”