Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Cancer. 2019 Apr 1;125(7):1060-1069. doi: 10.1002/cncr.31908. Epub 2018 Dec 12.
An inherited susceptibility to renal cancers is associated with multiple predisposing genes, but most screening tests are limited to patients with a family history. Next-generation sequencing (NGS)-based multigene panels provide an efficient and adaptable tool for investigating pathogenic germline mutations on a larger scale. This study investigated the frequency of pathogenic germline mutations in renal cancer predisposition genes in patients with sporadic, early-onset disease.
An NGS-based panel of 23 known and potential renal cancer predisposition genes was used to analyze germline mutations in 190 unrelated Chinese patients under the age of 45 years who presented with renal tumors. The detected variants were filtered for pathogenicity, and then their frequencies were calculated and correlated with clinical features. Germline variants of the fumarate hydratase (FH) and BRCA1-associated protein 1 (BAP1) genes were comprehensively analyzed because of their aggressive potential.
In total, 18 patients (9.5%) had germline mutations in 10 genes. Twelve of these 18 patients had alterations in renal cancer predisposition genes (6.3%), and 6 patients had mutations in potential predisposition genes such as BRCA1/2. Notably, pathogenic mutation carriers had a significant family history in second-degree relatives in comparison with those without pathogenic mutations (P < .001). Variants of unknown clinical significance in FH and BAP1 demonstrated evidence of additional somatic loss in tumors.
In patients with early-onset disease, a multigene panel identified a high pathogenic germline mutation rate in renal cancer predisposition genes. This study emphasizes the importance of screening patients with early-onset disease for mutations in cancer predisposition genes. Germline screening should be encouraged in early-onset patients to provide personalized medicine and improve patient outcomes.
遗传性易患肾癌与多个易患基因相关，但大多数筛查试验仅限于有家族史的患者。基于下一代测序（NGS）的多基因panel 为大规模研究致病性种系突变提供了一种高效且适应性强的工具。本研究调查了散发性、早发性疾病患者中肾癌易患基因的致病性种系突变频率。
采用基于 NGS 的 23 个已知和潜在的肾癌易患基因 panel 分析了 190 名年龄在 45 岁以下的、患有肾肿瘤的无血缘关系的中国患者的种系突变。对检测到的变异进行致病性过滤，然后计算其频率并与临床特征相关联。由于其侵袭性潜能，全面分析了富马酸水解酶（FH）和 BRCA1 相关蛋白 1（BAP1）基因的种系变异。
总共 18 名患者（9.5%）的 10 个基因存在种系突变。其中 12 名患者的肾癌易患基因发生了改变（6.3%），6 名患者的潜在易患基因如 BRCA1/2 发生了突变。值得注意的是，与未携带致病性突变的患者相比，致病性突变携带者的二级亲属有显著的家族史（P<.001）。FH 和 BAP1 中的意义不明的变异体在肿瘤中表现出额外的体细胞缺失证据。
在早发性疾病患者中，多基因 panel 确定了肾癌易患基因中存在高致病性种系突变率。本研究强调了对早发性疾病患者进行癌症易患基因突变筛查的重要性。应鼓励早发性患者进行种系筛查，以提供个体化治疗并改善患者预后。
