Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
PLoS Genet. 2018 Apr 16;14(4):e1007355. doi: 10.1371/journal.pgen.1007355. eCollection 2018 Apr.
Considering that mutations in known prostate cancer (PrCa) predisposition genes, including those responsible for hereditary breast/ovarian cancer and Lynch syndromes, explain less than 5% of early-onset/familial PrCa, we have sequenced 94 genes associated with cancer predisposition using next generation sequencing (NGS) in a series of 121 PrCa patients. We found monoallelic truncating/functionally deleterious mutations in seven genes, including ATM and CHEK2, which have previously been associated with PrCa predisposition, and five new candidate PrCa associated genes involved in cancer predisposing recessive disorders, namely RAD51C, FANCD2, FANCI, CEP57 and RECQL4. Furthermore, using in silico pathogenicity prediction of missense variants among 18 genes associated with breast/ovarian cancer and/or Lynch syndrome, followed by KASP genotyping in 710 healthy controls, we identified "likely pathogenic" missense variants in ATM, BRIP1, CHEK2 and TP53. In conclusion, this study has identified putative PrCa predisposing germline mutations in 14.9% of early-onset/familial PrCa patients. Further data will be necessary to confirm the genetic heterogeneity of inherited PrCa predisposition hinted in this study.
考虑到已知的前列腺癌（PrCa）易感性基因（包括导致遗传性乳腺癌/卵巢癌和林奇综合征的基因）的突变解释了不到 5%的早发性/家族性 PrCa，我们使用下一代测序（NGS）对 121 例 PrCa 患者中的 94 个与癌症易感性相关的基因进行了测序。我们发现了七个基因中的单等位基因截断/功能缺失突变，包括 ATM 和 CHEK2，这些基因先前与 PrCa 易感性相关，以及五个涉及癌症易感性隐性疾病的新候选 PrCa 相关基因，即 RAD51C、FANCD2、FANCI、CEP57 和 RECQL4。此外，通过对与乳腺癌/卵巢癌和/或林奇综合征相关的 18 个基因中的错义变异进行计算机预测的致病性，并对 710 名健康对照进行 KASP 基因分型，我们在 ATM、BRIP1、CHEK2 和 TP53 中发现了“可能致病”的错义变异。总之，本研究在 14.9%的早发性/家族性 PrCa 患者中发现了潜在的 PrCa 易感性种系突变。需要进一步的数据来证实本研究中暗示的遗传性 PrCa 易感性的遗传异质性。
