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.
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.
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.
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.
Genetics in medicine : official journal of the American College of Medical Genetics. 2021 Jan 13 [Epub ahead of print]
María Santos, Javier Lanillos, Juan María Roldan-Romero, Eduardo Caleiras, Cristina Montero-Conde, Alberto Cascón, Miguel Angel Climent, Georgia Anguera, Susana Hernando, Nuria Laínez, Mercedes Robledo, Luis Robles, Guillermo de Velasco, Jesús García-Donas, Cristina Rodriguez-Antona
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., Department of Medical Oncology, Instituto Valenciano de Oncología, Valencia, Spain., Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain., Department of Medical Oncology, Hospital Universitario Fundacion Alcorcon, Alcorcón, Madrid, Spain., Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain., Department of Medical Oncology, University Hospital 12 de Octubre, Madrid, Spain., Genitourinary and Gynecological Cancer Unit, HM Hospitales - Centro Integral Oncológico HM Clara Campal, Madrid, Spain., Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. .