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

TitleA germline FANCA alteration that is associated with increased sensitivity to DNA damaging agents.
Publication TypeJournal Article
Year of Publication2017
AuthorsWilkes DC, Sailer V, Xue H, Cheng H, Collins CC, Gleave M, Wang Y, Demichelis F, Beltran H, Rubin MA, Rickman DS
JournalCold Spring Harb Mol Case Stud
Volume3
Issue5
Date Published2017 Sep
ISSN2373-2873
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.

DOI10.1101/mcs.a001487
Alternate JournalCold Spring Harb Mol Case Stud
PubMed ID28864460