Malignant mixed mullerian tumor of the ovary and bilateral breast cancer: an argument for BRCA3, or a coincidental cluster of unconnected cancers?

OBJECTIVES: Malignant mixed mullerian tumors (MMMTs) of the ovary are a rare, aggressive subtype of ovarian cancer without a clear relationship to familial breast-ovarian cancer syndromes. CASE: We present the case of a woman with bilateral breast cancers who subsequently developed a stage IIIc MMMT of the ovary. The patient had a first-degree female relative with breast and ovarian cancer (not MMMT), as well as second- and third-degree female relatives each with bilateral breast cancers. BRCA1 and BRCA2 sequencing of germline DNA revealed no evidence of a heritable mutation. CONCLUSIONS: Ovarian MMMTs may be a hallmark of breast/ovarian cancer secondary to genetic risk independent of classic BRCA1/2 pathways.

Ovarian cancer BRCA1 mutation detection: Protein truncation test (PTT) outperforms single strand conformation polymorphism analysis (SSCP).

Recent studies have shown that the BRCA1 tumor suppressor gene plays a role in the development of both hereditary and sporadic ovarian cancer. Since several different mechanisms may give rise to tumor gene defects, a better understanding of these mechanisms may identify BRCA1 as an attractive therapeutic target in ovarian cancer. Sequencing this large gene is not practical on a population-wide basis. The optimal screening strategy is yet to be determined. The purpose of our study is to compare two common screening techniques: the protein truncation test (PTT) and single strand conformational polymorphism analysis (SSCP). Ninety-four patients with epithelial ovarian cancer and available snap-frozen tissue were screened for BRCA1 mutations by both PTT (five individual PCR reactions with complete translation of the product in the TNT System (Promega, Madison, WI)) and SSCP (41 individual PCR reactions covering the entire coding sequence). All abnormal results were confirmed by sequencing. A paired peripheral blood DNA sample was utilized to determine if the sequence abnormality was a germline mutation. Twenty-three mutations in BRCA1 were found in 22 patients (14 germline, eight somatic, one unknown) including four novel mutations: E489X, 3558delT, 3871delGTCT, del exon 7-10. Although the predictive value of a negative test was close for the two methods (PTT 99.1%, SSCP 99.8%), the comparison of positive predictive value overwhelmingly favored PTT (100.0%, vs. 26.4%, respectively). The specificity for PTT was 100.0% while the sensitivity was 82.6%. While for SSCP, the specificity was 99.0% and the sensitivity was only 60.9%. The concordance rate for the two screening tests was 88.9%. Only SSCP can detect missense mutations. PTT is a superior screening test for truncating BRCA1 mutations that are expected to be of clinical significance.

The p53 mutational spectrum associated with BRCA1 mutant ovarian cancer.

PURPOSE: Cancer-specific p53 mutational spectra have been identified. Data from murine models and human BRCA1-related hereditary breast cancers suggest that both unique and specific BRCA1-associated p53 mutations may be found in BRCA1-related ovarian cancers. EXPERIMENTAL DESIGN: The p53 mutational spectrum from ovarian cancers containing either somatic or germ-line BRCA1 mutations was compared with that of sporadic ovarian cancers defined as those diagnosed with a negative family history for breast/ovarian cancer in a three-generation pedigree. Tumor DNA was screened over exons 2-11 of the p53 gene by the PCR and single-strand confirmation polymorphism analysis of the amplimers. Cycle-based DNA sequencing from separate reactions was used to confirm p53 mutations. RESULTS: p53 gene mutations were detected in 42 of 86 sporadic ovarian cancers, compared with 13 of 15 cancers with somatic BRCA1 mutations (P = 0.007) and 16 of 20 cancers with germ-line BRCA1 mutations (P = 0.01). p53 null mutations were found in 31.4% of BRCA1 mutant cancers, compared with only 9.3% of the sporadic cancers (P = 0.002). The p53 mutational spectrum of germ-line BRCA1-related cancers was shifted toward transversions, frameshifts, and non-CpG transitions relative to the spectrum of sporadic ovarian cancers. Thirty-three unique ovarian cancer p53 mutations were sequenced. However, the specific p53 mutations in the BRCA1 mutant cancers were no more unique to this cohort than the p53 mutations of the sporadic cancers. CONCLUSIONS: Ovarian cancers containing somatic or germ-line BRCA1 mutations are uniformly accompanied by p53 dysfunction. This finding offers additional support to observations regarding the importance of p53/BRCA1 interactions in ovarian carcinogenesis.