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Methylation not a frequent "second hit" in tumors with germline BRCA mutations. Fam Cancer 2009;8(4):339-46



Pubmed ID




Scopus ID

2-s2.0-70449534798   48 Citations


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 approximately 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.

Author List

Dworkin AM, Spearman AD, Tseng SY, Sweet K, Toland AE


Andrew Spearman MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Base Sequence
Breast Neoplasms
DNA Methylation
Genes, BRCA1
Genes, BRCA2
Genetic Predisposition to Disease
Germ-Line Mutation
Loss of Heterozygosity
Ovarian Neoplasms
Polymorphism, Restriction Fragment Length
Promoter Regions, Genetic