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.
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Clinical and sequencing data are presented in Supplementary Materials and additional information can be provided upon request.
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This work was supported by the projects RTI2018-095039-B-I00 (Spanish Ministry of Science and Innovation [MCI/AEI], cofunded by the European Regional Development Fund [ERDF]). We thank Dr. Osorio and Dr. Urioste for their work on variant interpretation and Rocío Letón and Fátima Mercadillo for their technical assistance in the MLPA performance. We acknowledge Histopathology Core Unit from the Spanish National Cancer Research Center (CNIO) for their technical support.
The project was approved by the institutional review board (IRB) at Instituto de Salud Carlos III (PI 46_2019-v2) and each of the ethical review boards of the participating hospitals (Hospital 12 de Octubre, Hospital Universitario Fundacion Alcorcón, Fundació Althaia-Manresa, Complejo Hospitalario de Navarra, Hospital Universitario HM Sanchinarro, Hospital Clinic i Provincial de Barcelona, Hospital Clinico San Carlos, Complejo Hospitalario de Jaén, Hospital Universitario de Fuenlabrada, Hospital General de Asturias, Hospital Gregorio Marañón, Hospital Infanta Sofía, Hospital Ramón y Cajal, Hospital de la Santa Creu i Sant Pau, Hospital Virgen Rocio, Hospital del Mar, Hospital Universitario Central de Asturias, Hospital Universitario La Paz, Instituto Catalán de Oncología Badalona, Instituto Valenciano de Oncología, Hospital Morales Meseguer, Hospital Universitario Parc Taulí, Hospital Universitario Son Dureta, Hospital Son Llàtzer, Hospital Universitario Virgen de Valme). Written informed consent was obtained from all study patients. The study adheres to the principles set out in the Declaration of Helsinki.
G.A. reports the following competing interests: speakers’ bureau (Kyowa kyrin, Janssen, Bristol Myers Squibb, Roche, Sanofi, Rovi); travel grants (Roche, MSD, Pfizer, Novartis, Astellas, Janssen, Bristol Myers Squibb). G.d.V. reports the following competing interests: receipt of grants/research supports (Ipsen, Pfizer, Roche); receipt of honoraria or consultation fees (Ipsen, Pfizer, Roche, MSD, Merk, Astellas, Jannsen, Novartis, Bayer, BMS). The other authors declare no competing interests.
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Santos, M., Lanillos, J., Roldan-Romero, J.M. et al. Prevalence of pathogenic germline variants in patients with metastatic renal cell carcinoma. Genet Med (2021). https://doi.org/10.1038/s41436-020-01062-0