Identification of BRCA1 and BRCA2 genetic modifiers.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #1040 Background: Although mutations in BRCA1 and BRCA2 represent the primary lesions in hereditary breast and ovarian cancer (HBOC) families, these mutations are marked by incomplete penetrance, as 15-20% of carriers never develop either cancer. In addition, the expressivity of these gene mutations varies with manifestation in breast, ovary, or both breast and ovary, suggesting other genes may modify the effects of BRCA1 and BRCA2 mutations. Methods: DNA was isolated from nine large HBOC families with known BRCA1 and BRCA2 mutations. SNP data was generated using the GeneChip Mapping 10K Array (Affymetrix, Santa Clara, CA). The data were checked for deviation from Hardy-Weinberg equilibrium and Mendelian errors. SNPs with low completion rates were not used in the analyses. Two-point parametric linkage analysis was performed under dominant and recessive models using VITESSE and GAS. Results: Genotypes were generated for 301 individuals from nine families and included mutation carriers, and non-carriers with and without cancer. When all families were considered together using a dominant model, LOD scores >3.0 were detected for SNPs on chromosomes 6q25.3 and 18q21.3 and >2.0 for chromosomes 2q24, 5p13 and 5q33. When families were segregated by mutation type, linkage was detected at chromosome 22q12 (LOD =2.65) in BRCA1 families, and at 2q24 (LOD=2.17) in BRCA2 families. Conclusions: Chromosomal regions harboring putative genetic modifiers have been identified that may contribute to pathogenesis in both BRCA1 and BRCA2 families. For example, frequent gain of 2q24 has been detected in BRCA1 carriers with ovarian cancer, loss of 5q in breast tumors from BRCA1 patients, and SNP [rs720321][1] is intragenic to the apoptosis gene BCL2 on chromosome 18q21, expression of which has been associated with BRCA2 tumors. Linkage to chromosome 22q12 was specific to BRCA1 families, of note, the loss of the CHEK2 gene, located on chromosome 22q12, may promote tumor progression in BRCA1 tumors. Further elucidation of the underlying genetic lesion from each of these chromosomal regions may improve the risk assessment and treatment regimens of women with BRCA1 and BRCA2 mutations. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1040. [1]: /lookup/external-ref?link_type=GEN&access_num=rs720321&atom=%2Fcanres%2F69%2F2_Supplement%2F1040.atom