Cancer Genetics Group, IPO Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, Porto, Portugal.
Genome Center, University of California at Davis, Davis, CA, USA.
Br J Cancer. 2023 Apr;128(6):1077-1085. doi: 10.1038/s41416-022-02125-6. Epub 2022 Dec 23.
Prostate cancer (PrCa) is one of the most hereditable human cancers, however, only a small fraction of patients has been shown to carry deleterious variants in known cancer predisposition genes.
Whole-exome sequencing was performed in multiple affected members of 45 PrCa families to select the best candidate genes behind part of the PrCa missing hereditability. Recurrently mutated genes were prioritised, and further investigated by targeted next-generation sequencing in the whole early-onset and/or familial PrCa series of 462 patients.
PRUNE2 stood out from our analysis when also considering the available data on its association with PrCa development. Ten germline pathogenic/likely pathogenic variants in the PRUNE2 gene were identified in 13 patients. The most frequent variant was found in three unrelated patients and identical-by-descent analysis revealed that the haplotype associated with the variant is shared by all the variant carriers, supporting the existence of a common ancestor.
This is the first report of pathogenic/likely pathogenic germline variants in PRUNE2 in PrCa patients, namely in those with early-onset/familial disease. Importantly, PRUNE2 was the most frequently mutated gene in the whole series, with a deleterious germline variant identified in 2.8% of the patients, representing a novel prostate cancer predisposition gene.
前列腺癌（PrCa）是最具遗传性的人类癌症之一，但只有一小部分患者被证明携带已知癌症易感性基因中的有害变异。
对 45 个 PrCa 家族的多个受影响成员进行全外显子组测序，以选择部分缺失遗传易感性的最佳候选基因。对反复突变的基因进行优先排序，并在 462 例早发性和/或家族性 PrCa 全系列中通过靶向下一代测序进一步研究。
当还考虑到 PRUNE2 与 PrCa 发展相关的可用数据时，PRUNE2 从我们的分析中脱颖而出。在 13 名患者中发现了 PRUNE2 基因中的 10 个种系致病性/可能致病性变异。最常见的变异在三个无血缘关系的患者中发现，并且相同的遗传分析显示，与变体相关的单倍型由所有变体携带者共享，支持存在共同的祖先。
这是首次在 PrCa 患者中报告 PRUNE2 中的致病性/可能致病性种系变异，即在早发性/家族性疾病患者中。重要的是，PRUNE2 是整个系列中突变最频繁的基因，在 2.8%的患者中发现了有害的种系变异，代表了一个新的前列腺癌易感性基因。
