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


CONCLUSIONS
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.
Conde
João
J
Department of Genetics, Faculty of Medical Sciences, New University of Lisbon, Rua da Junqueira 96, P-1349-008 Lisboa, Portugal. conde.bio@gmail.com
Silva
Susana N
SN
Azevedo
Ana P
AP
Teixeira
Valdemar
V
Pina
Julieta Esperança
JE
Rueff
José
J
Gaspar
Jorge F
JF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D016022:Case-Control Studies; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D004198:Disease Susceptibility; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D005810:Multigene Family; D011110:Polymorphism, Genetic; D011174:Portugal
D045643:DNA Repair Enzymes