Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype

Overview

Journal Cancer Discov

Specialty Oncology

Date 2014 Dec 5

PMID 25472942

Citations 183

Authors

Sarah L Sawyer

Lei Tian

Marketta Kahkonen

Jeremy Schwartzentruber

Martin Kircher

Jacek Majewski

David A Dyment

A Micheil Innes

Kym M Boycott

Lisa A Moreau

Jukka S Moilanen

Roger A Greenberg

Affiliations

Soon will be listed here.

Abstract

Unlabelled: Deficiency in BRCA-dependent DNA interstrand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome Fanconi anemia. Bona fide Fanconi anemia proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ), interact with BRCA1 during ICL repair. However, the lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive Fanconi anemia susceptibility gene. Here, we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a Fanconi anemia-like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 and RAD51 localization to DNA-damage sites, combined with radial chromosome formation and hypersensitivity to ICL-inducing agents. Restoration of these functions was achieved by ectopic introduction of a BRCA1 transgene. These observations provide evidence in support of BRCA1 as a new Fanconi anemia gene (FANCS).

Significance: We establish that biallelic BRCA1 mutations cause a distinct FA-S, which has implications for risk counselling in families where both parents harbor BRCA1 mutations. The genetic basis of hereditary cancer susceptibility syndromes provides diagnostic information, insights into treatment strategies, and more accurate recurrence risk counseling to families.

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