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

Wilkes, David C; Sailer, Verena; Xue, Hui; Cheng, Hongwei; Collins, Colin C; Gleave, Martin; Wang, Yuzhuo; Demichelis, Francesca; Beltran, Himisha; Rubin, Mark Andrew; Rickman, David S (2017). A germline FANCA alteration that is associated with increased sensitivity to DNA damaging agents. Cold Spring Harbor molecular case studies, 3(5) Cold Spring Harbor Laboratory Press 10.1101/mcs.a001487

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

UniBE Contributor:

Rubin, Mark Andrew

Subjects:

500 Science
500 Science > 570 Life sciences; biology

ISSN:

2373-2873

Publisher:

Cold Spring Harbor Laboratory Press

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

08 Mar 2018 13:02

Last Modified:

23 Oct 2019 14:34

Publisher DOI:

10.1101/mcs.a001487

PubMed ID:

28864460

Uncontrolled Keywords:

prostate cancer

BORIS DOI:

10.7892/boris.110751

URI:

https://boris.unibe.ch/id/eprint/110751

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