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Open Access Highly Accessed Research article

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

João Conde1, Susana N Silva1, Ana P Azevedo23, Valdemar Teixeira3, Julieta Esperança Pina4, José Rueff1* and Jorge F Gaspar1*

Author Affiliations

1 Department of Genetics, Faculty of Medical Sciences, New University of Lisbon. Rua da Junqueira 96. P-1349-008 Lisboa, Portugal

2 Department of Biochemistry, Faculty of Medical Sciences, New University of Lisbon. Campo dos Mártires da Pátria 130, 1169-056 Lisboa, Portugal

3 Department of Clinical Pathology, Hospital de S. Francisco Xavier, Estrada do Forte do Alto do Duque, 1495-005 Lisboa, Portugal

4 Department of Laboratorial Medicine, Faculty of Medical Sciences, New University of Lisbon, Hospital de S. Francisco Xavier, Estrada do Forte do Alto do Duque, 1495-005 Lisboa, Portugal

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BMC Cancer 2009, 9:344  doi:10.1186/1471-2407-9-344

Published: 25 September 2009

Abstract

Background

MMR 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.

Methods

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).

Results

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.

Conclusion

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.