Germline mutations of renal cancer predisposition genes and clinical relevance in Chinese patients with sporadic, early-onset disease.
Germline mutations of renal cancer predisposition genes and clinical relevance in Chinese patients with sporadic, early-onset disease.
复制标题
中国散发性早发性疾病患者肾癌易感基因的种系突变及其临床相关性。
作者：
Wu J;Wang H;Ricketts CJ;Yang Y;Merino MJ;Zhang H;Shi G;Gan H;Linehan WM;Zhu Y;Ye D
肾癌的遗传易感性与多种易感基因有关，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）的多基因组为更大规模地研究致病性种系突变提供了一种有效且适应性强的工具。本研究调查了散发性早发性肾癌患者中肾癌易感基因的致病性种系突变频率。使用基于NGS的23个已知和潜在的肾癌易感基因组来分析190名45岁以下无血缘关系的中国肾肿瘤患者的种系突变。对检测到的变异体进行致病性筛选，然后计算其频率并与临床特征相关联。由于富马酸水合酶（FH）和BRCA 1相关蛋白1（BAP 1）基因的侵袭潜力，对其种系变异体进行了全面分析。总共有18名患者（9.5%）在10个基因中存在生殖系突变。这18例患者中有12例（6.3%）存在肾癌易感基因的改变，6例患者存在潜在易感基因（如BRCA 1/2）的突变。值得注意的是，致病性突变携带者与无致病性突变者相比，在二级亲属中有显著的家族史（P <0.001）。FH和BAP 1中临床意义未知的变异体证明了肿瘤中额外的体细胞丢失的证据。在早发性疾病患者中，多基因组鉴定出肾癌易感基因中的高致病性种系突变率。这项研究强调了筛查早发性疾病患者癌症易感基因突变的重要性。应鼓励在早发性患者中进行生殖系筛查，以提供个性化药物并改善患者结局。
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.
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DOI：
10.2147/ijnrd.s42097
发表时间：
2014
影响因子：
2
作者：
Schmidt LS;Linehan WM
通讯作者：
Linehan WM
影响因子：
45.3
作者：
Shuch, Brian;Vourganti, Srinivas;Linehan, W. Marston
通讯作者：
Linehan, W. Marston
影响因子：
0.4
作者：
Sameer, A. S.;Shah, Z. A.;Siddiqi, M. A.
通讯作者：
Siddiqi, M. A.
影响因子：
168.9
作者：
Bissler, John J.;Kingswood, J. Christopher;Budde, Klemens
通讯作者：
Budde, Klemens
影响因子：
64.8
作者：
通讯作者：
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