Mutations in DNA repair genes have been connected with familial prostate cancer and sensitivity to targeted drugs like PARP-inhibitors. Clinical use of this information is limited by the small fraction of prostate cancer risk gene carriers, variants of unknown pathogenicity and the focus on monogenic disease mechanisms. Functional assays capturing mono- and polygenic defects were shown to detect breast and ovarian cancer risk in blood-derived cells. Here, we comparatively analyzed lymphocytes from prostate cancer patients and controls applying a sensitive DNA double-strand break (DSB) repair assay and a flow cytometrybased assay measuring the activity of Poly(ADP-Ribose)-Polymerase, a target in treatment of metastatic prostate cancer. Contrary to breast and ovarian cancer patients, error-prone DNA double-strand break repair was not activated in prostate cancer patients. Yet, the activity of PARP discriminated between prostate cancer cases and controls. PARylation also correlated with the age of male probands, suggesting male-specific links between mutation-based and aging-associated DNA damage accumulation and PARP. Our work identifies prostate cancer-specific DNA repair phenotypes characterized by increased PARP activities and carboplatin-sensitivities, detected by functional testing of lymphocytes. This provides new insights for further investigation of PARP and carboplatin sensitivity as biomarkers in peripheral cells of men and prostate cancer patients.

DNA 修复基因的突变与家族性前列腺癌和对 PARP 抑制剂等靶向药物的敏感性有关。该信息的临床使用受到前列腺癌风险基因携带者的一小部分、未知致病性的变异和对单基因疾病机制的关注的限制。捕获单基因和多基因缺陷的功能测定被证明可以检测血液衍生细胞中的乳腺癌和卵巢癌风险。在这里，我们比较分析了来自前列腺癌患者和对照的淋巴细胞，应用敏感的 DNA 双链断裂 (DSB) 修复测定和基于流式细胞术的测定来测量聚（ADP-核糖）-聚合酶的活性，聚（ADP-核糖）-聚合酶是治疗转移性前列腺的靶点癌症。与乳腺癌和卵巢癌患者相反，容易出错的 DNA 双链断裂修复在前列腺癌患者中没有被激活。然而，PARP 的活性区分了前列腺癌病例和对照。PARylation 还与男性先证者的年龄相关，表明基于突变和衰老相关的 DNA 损伤积累与 PARP 之间存在男性特异性联系。我们的工作确定了前列腺癌特异性 DNA 修复表型，其特征是通过淋巴细胞功能测试检测到的 PARP 活性和卡铂敏感性增加。这为进一步研究作为男性和前列腺癌患者外周细胞生物标志物的 PARP 和卡铂敏感性提供了新的见解。表明基于突变和衰老相关的 DNA 损伤积累与 PARP 之间存在男性特异性联系。我们的工作确定了前列腺癌特异性 DNA 修复表型，其特征是通过淋巴细胞功能测试检测到的 PARP 活性和卡铂敏感性增加。这为进一步研究作为男性和前列腺癌患者外周细胞生物标志物的 PARP 和卡铂敏感性提供了新的见解。表明基于突变和衰老相关的 DNA 损伤积累与 PARP 之间存在男性特异性联系。我们的工作确定了前列腺癌特异性 DNA 修复表型，其特征是通过淋巴细胞功能测试检测到的 PARP 活性和卡铂敏感性增加。这为进一步研究作为男性和前列腺癌患者外周细胞生物标志物的 PARP 和卡铂敏感性提供了新的见解。