转移性肾细胞癌患者种系致病变异的流行率。

Prevalence of pathogenic germline variants in patients with metastatic renal cell carcinoma.

机构信息

Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

Histopathology Core Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

出版信息

Genet Med. 2021 Apr;23(4):698-704. doi: 10.1038/s41436-020-01062-0. Epub 2021 Jan 13.

DOI:10.1038/s41436-020-01062-0

PMID:33442023

Abstract

PURPOSE

Germline pathogenic variants are estimated to affect 3-5% of renal cell carcinoma (RCC) patients. However, higher mutational prevalence in non-clear cell RCC (non-ccRCC) and advanced disease has been suggested.

METHODS

To clarify the prevalence of pathogenic germline variants in metastatic RCC, we sequenced 29 cancer susceptibility genes in 294 unselected metastatic RCC cases plus 21 patients with clinical hereditary features. In 145 tumors, genes frequently mutated in RCC were sequenced and methylation was assessed in selected cases.

RESULTS

Germline variants in RCC predisposition genes (FH, VHL) were detected in 1.4% of the unselected metastatic patients, with higher frequency in non-ccRCC versus ccRCC (6.4% and 0.4%; P = 0.0025) and in younger patients (P = 0.036). Among the 315 studied patients, 14% of non-type 1 papillary cases (4 of 28), all metastatic <1 year after diagnosis, carried a FH germline variant with loss of heterozygosity and tumor genome hypermethylation. Variants in other cancer-associated genes (e.g., MUTYH, BRCA2, CHEK2) occurred in 5.1% of the unselected series, with unclear significance for RCC.

CONCLUSION

Our findings confirm a high prevalence of pathogenic germline variants in RCC predisposition genes in metastatic non-ccRCC, and highlight that metastatic patients with papillary type 2 or unconventional histologies compatible with FH would benefit from genetic screening.

摘要

目的

胚系致病性变异估计影响 3-5%的肾细胞癌（RCC）患者。然而，在非透明细胞 RCC（非 ccRCC）和晚期疾病中，突变的患病率更高。

方法

为了阐明转移性 RCC 中致病性种系变异的流行率，我们对 294 例未经选择的转移性 RCC 病例和 21 例具有临床遗传性特征的患者进行了 29 个癌症易感性基因的测序。在 145 个肿瘤中，对 RCC 中经常发生突变的基因进行了测序，并在选定的病例中评估了甲基化。

结果

在未经选择的转移性患者中，RCC 易感性基因（FH、VHL）的种系变异发生率为 1.4%，非 ccRCC 与 ccRCC 的发生率较高（6.4%和 0.4%；P=0.0025），且在年轻患者中发生率较高（P=0.036）。在 315 例研究患者中，14%的非 1 型乳头状病例（28 例中有 4 例），所有在诊断后 1 年内转移，携带 FH 种系变异，存在杂合性丢失和肿瘤基因组甲基化。在其他癌症相关基因（如 MUTYH、BRCA2、CHEK2）中的变异在未经选择的系列中发生率为 5.1%，对 RCC 的意义不明确。