Biallelic Deleterious BRCA1 Mutations in a Woman with Early-onset Ovarian Cancer

Overview

Journal Cancer Discov

Specialty Oncology

Date 2012 Dec 28

PMID 23269703

Citations 80

Authors

Susan M Domchek

Jiangbo Tang

Jill Stopfer

Dana R Lilli

Nancy Hamel

Marc Tischkowitz

Alvaro N A Monteiro

Troy E Messick

Jacquelyn Powers

Alexandria Yonker

Fergus J Couch

David E Goldgar

H Rosemarie Davidson

Katherine L Nathanson

William D Foulkes

Roger A Greenberg

Affiliations

Soon will be listed here.

Abstract

Unlabelled: BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in BRCA2 can lead to Fanconi anemia and predisposition to cancers, whereas biallelic BRCA1 mutations have not been confirmed, presumably because one wild-type BRCA1 allele is required during embryogenesis. This study describes an individual who was diagnosed with ovarian carcinoma at age 28 and found to have one allele with a deleterious mutation in BRCA1, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala cosegregated with cancer in multiple families, associated tumors showed loss of wild-type BRCA1, and BRCA1 p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human BRCA1 mutations and have implications for the interpretation of genetic test results.

Significance: Accurate assessment of genetic testing data for BRCA1 mutations is essential for clinical monitoring and treatment strategies. Here, we report the fi rst validated example of an individual with biallelic BRCA1 mutations, early-onset ovarian cancer, and clinically significant hypersensitivity to chemotherapy.

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