Association of BRCA1/2 mutations with ovarian cancer prognosis: An updated meta-analysis.
Ontology highlight
ABSTRACT:
SUBMITTER: Huang YW
PROVIDER: S-EPMC5943891 | biostudies-other | 2018 Jan
REPOSITORIES: biostudies-other
Publications
Association of BRCA1/2 mutations with ovarian cancer prognosis: An updated meta-analysis.
Medicine 20180101 2
<h4>Objective</h4>A meta-analysis was performed to determine if BRCA1/2 mutations are associated with improved overall survival (OS) and progression-free survival (PFS) in patients with ovarian cancer.<h4>Research design and methods</h4>Studies of patients with primary or recurrent ovarian cancer that examined the relationship between BRCA1/2 mutation status and outcomes were included.<h4>Main outcome measures</h4>The primary outcomes were OS and PFS of patients with and without BRCA1 and BRCA2 ...[more]
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Project description:Germline mutations in the breast and ovarian cancer susceptibility gene BRCA1 are responsible for the majority of cases involving hereditary breast and ovarian cancer. Whereas all truncating mutations are considered as functionally deleterious, most of the missense variants identified to date cannot be readily distinguished as either disease-associated mutations or benign polymorphisms. The C-terminal domain of BRCA1 displays an intrinsic transactivation activity, and mutations linked to disease predisposition have been shown to confer loss of such activity in yeast and mammalian cells. In an attempt to clarify the functional importance of the BRCA1 C-terminus as a transcription activator in cancer predisposition, we have characterized the effect of C-terminal germline variants identified in Scandinavian breast and ovarian cancer families. Missense variants A1669S, C1697R, R1699W, R1699Q, A1708E, S1715R and G1738E and a truncating mutation, W1837X, were characterized using yeast- and mammalian-based transcription assays. In addition, four additional missense variants (V1665M, D1692N, S1715N and D1733G) and one in-frame deletion (V1688del) were included in the study. Our findings demonstrate that transactivation activity may reflect a tumor-suppressing function of BRCA1 and further support the role of BRCA1 missense mutations in disease predisposition. We also report a discrepancy between results from yeast- and mammalian-based assays, indicating that it may not be possible to unambiguously characterize variants with the yeast assay alone. We show that transcription-based assays can aid in the characterization of deleterious mutations in the C-terminal part of BRCA1 and may form the basis of a functional assay.
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Project description:ObjectiveBreast cancer susceptibility gene 1/2 (BRCA1/2) is the most important susceptibility gene associated with hereditary ovarian cancer (HOC). We aimed to screen BRAC1 and BRAC2 gene mutations in a member of a hereditary ovarian cancer family in China, and to analyze the structure and function of the mutant protein.MethodsA typical HOC family was selected. Blood samples and pathological tissue samples were taken from the female members of the family. Blood samples from two patients with sporadic ovaries of the same pathological type were taken as a control group. After RNA extraction, PCR amplification was applied and the PCR products were directly sequenced and aligned, prediction and analysis of protein structure and molecular conformation that may be caused by BRCA1/2 mutation.ResultsThe whole gene analysis of BRCA1 and BRCA2 in ovarian cancer patients in the family showed that there were 8 mutations in BRCA1 whole gene sequencing, including 3 nonsense mutations (2314C>T, 2543T>C, 4540T>C); two mutations have been recorded, which are associated with cervical cancer (2844C>T) and endometriosis (3345A>G); three newly discovered mutations (3780A>G, 5069A>G, 3326A>T). Among them, 3780A>G and 5069A>G caused amino acid changes, while 3326A>T mutation caused Arg mutation to stop codon. A total of 7 mutations were detected in BRCA2 whole-genome sequencing, including 5 non-significant mutations (3623A>G, 4034T>C, 4790A>G, 6740G>C, 7469A>G); one no-record mutation (1716T>A), and 1 recorded mutation (1342A>C), which was associated with breast cancer and ovarian cancer. BRCA1 (3326A>T) and BRCA2 (1342A>C) mutations were co-existing in patients (II1, II3, and II5) identified as serous adenocarcinoma grade II. Two cases of ovarian serous cystadenocarcinoma with no history of family tumors were normalized for BRCA1/2 gene sequencing. In the gene detection of III generation female, four females with BRCA2 (1342A>C) mutation were found, and one of them also carried the BRCA1 (3326A>T) mutation, who can be considered a high-risk group of HOC in this family. Online protein structure predictions revealed that BRCA1 (3326A>T) mutations mutated AGA at this site to TGA resulting in a translated Arg (arginine) mutation as a stop codon, while BRCA2 (1342A>C) mutated AAT at this site to CAT resulting in a translated Asn mutation to His.ConclusionThe BRCA1 (3326A>T) and BRCA2 (1342A>C) were detected in the HOC family, which may be the susceptibility gene of the family's HOC. The BRCA1/2 gene screening may be possible to obtain high-risk populations in this family.
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