Variants in DNA double-strand break repair genes and risk of familial breast cancer in a South American population

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作者
Lilian Jara
Karen Dubois
Daniel Gaete
Tomas de Mayo
Nikalai Ratkevicius
Teresa Bravo
Sonia Margarit
Rafael Blanco
Fernando Gómez
Enrique Waugh
Octavio Peralta
Jose M. Reyes
Gladys Ibáñez
Patricio González-Hormazábal
机构
[1] University of Chile,Human Genetics Program, Institute of Biomedical Sciences (ICBM), School of Medicine
[2] National Cancer Society (Corporación Nacional del Cáncer—CONAC),School of Medicine and Clínica Alemana
[3] Universidad del Desarrollo,Department of Gynaecology and Obstetrics, School of Medicine
[4] Clínica Santa María,undefined
[5] University of Chile,undefined
[6] Clínica Las Condes,undefined
[7] Clínica Dávila,undefined
[8] Hospital San José,undefined
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关键词
Familial BC; -Thr241Met; -E233G; 135G>C; Polymorphism;
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摘要
The double-strand break (DSB) DNA repair pathway has been implicated in breast cancer (BC). RAD51 and its paralogs XRCC3 and RAD51D play an important role in the repair of DSB through homologous recombination (HR). Some polymorphisms including XRCC3-Thr241Met, RAD51-135G>C, and RAD51D-E233G have been found to confer increased BC susceptibility. In order to detect novel mutations that may contribute to BC susceptibility, 150 patients belonging to 150 Chilean BRCA1/2-negative families were screened for mutations in XRCC3. No mutations were detected in the XRCC3 gene. In addition, using a case–control design we studied the XRCC3-Thr241Met, and RAD51D-E233G polymorphisms in 267 BC cases and 500 controls to evaluate their possible association with BC susceptibility. The XRCC3 Met/Met genotype was associated with an increased BC risk (P = 0.003, OR = 2.44 [95%CI 1.34–4.43]). We did not find an association between E233G polymorphism and BC risk. We also analyzed the effect of combined genotypes among RAD51-135G>C, Thr241Met, and E233G polymorphisms on BC risk. No interaction was observed between Thr241Met and 135G>C. The combined genotype Thr/Met–E/G was associated with an increased BC risk among women who (a) have a family history of BC, (b) are BRCA1/2-negative, and (c) were <50 years at onset (n = 195) (P = 0.037, OR = 10.5 [95%CI 1.16–94.5]). Our results suggested that the variability of the DNA HR repair genes XRCC3 and RAD51D may play a role in BC risk, but this role may be underlined by a mutual interaction between these genes. These findings should be confirmed in other populations.
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页码:813 / 822
页数:9
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