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Major Genes


Overall evidence suggests DCIS is part of the BRCA1/BRCA2 spectrum, particularly BRCA2; however, the prevalence of mutations in DCIS patients, unselected for family history, is less than 5%.[230,233]

BRCA2 Pathology

The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well-characterized than that of BRCA1, although they are generally positive for ER and PR.[202,206,237] A report from Iceland found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors compared with sporadic controls; however, a single BRCA2 founder mutation (999del5) accounts for nearly all hereditary breast cancer in this population, thus limiting the generalizability of this observation.[238] A large case series from North America and Europe described a greater proportion of BRCA2-associated tumors with continuous pushing margins, fewer tubules and lower mitotic counts.[239] Other reports suggest that BRCA2 related tumors include an excess of lobular and tubulolobular histology.[204,206] In summary, histologic characteristics associated with BRCA2 mutations have been inconsistent.

Pathology of Ovarian Cancer

Ovarian cancer arising in women with BRCA1 and BRCA2 mutations is more likely to be invasive serous adenocarcinoma, and less likely to be mucinous or borderline.[240,241,242] Fallopian tube cancer and papillary serous carcinoma of the peritoneum are also part of the spectrum of BRCA-associated disease.[62,243] Approximately 60% of sporadic ovarian cancers have serous histology, but a survey of all published data shows that 94% of BRCA1-related ovarian cancers have this type of histology.[185] Serous carcinoma was also found to be the predominant histologic subtype of intraperitoneal carcinoma among BRCA1/BRCA2 carriers in a Dutch case-control study.[244] In contrast to high-grade serous ovarian cancer, low-grade serous ovarian cancer is not likely to be part of the spectrum of BRCA1- or BRCA2-related ovarian cancer.[245] Both primary ovarian carcinomas and primary peritoneal carcinomas have a higher incidence of somatic TP53 mutations and exhibit relatively aggressive features, including higher grade and p53 overexpression.[240,246] The histopathologic profile of BRCA2 related ovarian cancer has not been well defined. The finding of differential expression of genes in BRCA1, BRCA2, and sporadic ovarian cancer, using DNA microarray technology, suggests distinct molecular pathways of carcinogenesis that may ultimately distinguish them histologically.[247] Furthermore, there have been data to suggest that BRCA-related ovarian cancers that relapse frequently metastasize to viscera, while relapsed sporadic ovarian cancers commonly remain confined to the peritoneum.[248]

There are now several lines of evidence indicating that primary fallopian tube cancer should be considered a part of the BRCA1/BRCA2phenotype. Histopathologic examination of fallopian tubes removed prophylactically from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that are accompanied by changes in cell-cycle and apoptosis-related proteins, suggesting a premalignant phenotype.[249,250]


WebMD Public Information from the National Cancer Institute

Last Updated: May 16, 2012
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