Abstract
Mutations in tumor suppressor genes BRCA1 and BRCA2 confer an increased lifetime risk of breast and ovarian cancer. Loss of heterozygosity (LOH) of the wildtype allele has been observed in ~80% of tumors from BRCA1 carriers and 70% of tumors from BRCA2 carriers and accounts for the majority of the “second-hits” occurring in BRCA-related tumors. Few sporadic tumors have been reported to have mutations in BRCA. Some sporadic tumors do show LOH of BRCA1 and BRCA2. BRCA1 promoter methylation has also been observed in sporadic ovarian and breast tumors; however, BRCA2 promoter methylation has not been reported in sporadic tumors. The relationship between BRCA LOH and BRCA promoter methylation has not been well characterized in tumors from BRCA germline mutation carriers. The goal of this study was to determine if BRCA1 and BRCA2 promoter hypermethylation serves as a “second-hit” in tumors from mutation carriers that do not show LOH. We studied 38 tumors from BRCA1 carriers and 23 tumors from BRCA2 carriers for LOH. To determine if BRCA1 and BRCA2 promoter hypermethylation serves as a “second-hit” in tumors with germline mutations, we tested 15 tumors lacking LOH and nine tumors with LOH for BRCA1 or BRCA2 promoter methylation. We identified seven BRCA1 tumors and nine BRCA2 tumors lacking LOH. Of these, only one tumor with a BRCA2 mutation showed promoter methylation. These data indicate that promoter methylation is a not a frequent “second-hit” in tumors from BRCA1 or BRCA2 carriers.
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Abbreviations
- LOH:
-
Loss of heterozygosity
- ER:
-
Estrogen receptor
- PR:
-
Progesterone receptor
- Her2:
-
Her2/Neu amplification status
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Acknowledgments
This work was funded in part by Mayers Summer Fellowship (AS) the National Institutes of Health, National Cancer Institute, Bay Area Breast Spore Career Development Award (P50 CA582017, AET) and funds from the OSU Comprehensive Cancer Center (AET). We thank Drs. S. Barsky, X.-P. Zhou, R. Jimenez, M. Abdel-Rahman, and B.-M. Ljung for reviewing pathology. F. Couch (Mayo Clinic Familial Cancer Program) and J. Ziegler, B. Crawford, J. McClennan (UCSF Familal Risk Shared Resource) provided samples for study. C. Reader (OSU CCC Tissue Procurement Shared Resource), K. Chew (UCSF Tissue Shared Resource), K. Gault, M. Means, A. De’Souza, I. Comeras (OSU Clinical Cancer Genetics) and S. Nagy (OSU Human Cancer Genetics Sample Bank) were instrumental in sample ascertainment and preparation. We thank the OSU CCC Nucleic Acids Shared Resource for sequencing support.
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Dworkin, A.M., Spearman, A.D., Tseng, S.Y. et al. Methylation not a frequent “second hit” in tumors with germline BRCA mutations. Familial Cancer 8, 339–346 (2009). https://doi.org/10.1007/s10689-009-9240-1
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DOI: https://doi.org/10.1007/s10689-009-9240-1