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Cold Spring Harb Mol Case Stud. 2017 Sep;3(5). pii: a001487. doi: 10.1101/mcs.a001487. Epub 2017 May 3.

A germline FANCA alteration that is associated with increased sensitivity to DNA damaging agents.

Author information

1
Englander Institute for Precision Medicine, Weill Cornell Medicine and New York-Presbyterian Hospital, New York, New York 10065, USA.
2
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
3
Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
4
Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
5
Centre for Integrative Biology, University of Trento, Trento, 38123, Italy.
6
Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York 10065, USA.
7
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065, USA.

Abstract

Defects in genes involved in DNA damage repair (DDR) pathway are emerging as novel biomarkers and targets for new prostate cancer drug therapies. A previous report revealed an association between an exceptional response to cisplatin treatment and a somatic loss of heterozygosity (LOH) of FANCA in a patient with metastatic prostate cancer who also harbored a germline FANCA variant (S1088F). Although germline FANCA mutations are the most frequent alterations in patients with Fanconi anemia, germline alterations are less common in prostate cancer. We hypothesized that the germline S1088F FANCA variant in combination with FANCA LOH was deleterious for FANCA function and contributed to the patient's exceptional response to cisplatin. We show that although it properly localizes to the nucleus, the S1088F FANCA mutant protein disrupts the FANC protein complex resulting in increased sensitivity to DNA damaging agents. Because molecular stratification is emerging as a strategy for treating men with metastatic, castrate-resistant prostate cancer harboring specific DDR gene defects, our findings suggest that more biomarker studies are needed to better define clinically relevant germline and somatic alterations.

KEYWORDS:

prostate cancer

PMID:
28864460
PMCID:
PMC5593159
DOI:
10.1101/mcs.a001487
[Indexed for MEDLINE]
Free PMC Article

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