A germline FANCA alteration that is associated with increased sensitivity to DNA damaging agents.
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.
['Wilkes|David C|DC|', 'Sailer|Verena|V|', 'Xue|Hui|H|', 'Cheng|Hongwei|H|', 'Collins|Colin C|CC|', 'Gleave|Martin|M|', 'Wang|Yuzhuo|Y|', 'Demichelis|Francesca|F|', 'Beltran|Himisha|H|', 'Rubin|Mark A|MA|', 'Rickman|David S|DS|']
D014408:Biomarkers, Tumor D045744:Cell Line, Tumor D002467:Cell Nucleus D002945:Cisplatin D004247:DNA D004268:DNA-Binding Proteins D005199:Fanconi Anemia D052217:Fanconi Anemia Complementation Group A Protein D006801:Humans D019656:Loss of Heterozygosity D008297:Male D009154:Mutation D009687:Nuclear Proteins D011471:Prostatic Neoplasms
prostate cancer