Wilkes David C, Sailer Verena, Xue Hui, Cheng Hongwei, Collins Colin C, Gleave Martin, Wang Yuzhuo, Demichelis Francesca, Beltran Himisha, Rubin Mark A, Rickman David S
Englander Institute for Precision Medicine, Weill Cornell Medicine and New York-Presbyterian Hospital, New York, New York 10065, USA.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
Cold Spring Harb Mol Case Stud. 2017 Sep;3(5). doi: 10.1101/mcs.a001487. Epub 2017 May 3.
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 in a patient with metastatic prostate cancer who also harbored a germline variant (S1088F). Although germline 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 variant in combination with 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.
参与DNA损伤修复（DDR）途径的基因缺陷正逐渐成为新型生物标志物以及前列腺癌新药物治疗的靶点。先前的一份报告显示，一名转移性前列腺癌患者对顺铂治疗有异常反应，且存在杂合性体细胞丢失（LOH），该患者还携带种系 变体（S1088F）。虽然种系 突变是范可尼贫血患者中最常见的改变，但种系改变在前列腺癌中不太常见。我们推测，种系S1088F 变体与LOH共同作用对FANCA功能有害，并导致患者对顺铂产生异常反应。我们发现，尽管S1088F FANCA突变蛋白能正确定位于细胞核，但它会破坏FANC蛋白复合物，导致对DNA损伤剂的敏感性增加。由于分子分层正成为治疗患有特定DDR基因缺陷的转移性、去势抵抗性前列腺癌男性患者的一种策略，我们的研究结果表明，需要更多的生物标志物研究来更好地定义临床相关的种系和体细胞改变。
