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



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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Fig. 1: Frequency of germline variants in an unselected cohort of 294 metastatic renal cell carcinoma (RCC) patients.
Fig. 2: Somatic variants in 11 tumors available from patients with a germline variant.
Fig. 3: Variants and expression of FH in papillary renal cell carcinoma (pRCC) and methylation status in the FH-mutated tumors.

Data availability

Clinical and sequencing data are presented in Supplementary Materials and additional information can be provided upon request.


  1. 1.

    Rini, B. I., Campbell, S. C. & Escudier, B. Renal cell carcinoma. Lancet. 373, 1119–1132 (2009).

    CAS  Article  Google Scholar 

  2. 2.

    Linehan, W. M., Walther, M. M. & Zbar, B. The genetic basis of cancer of the kidney. J. Urol. 170, 2163–2172 (2003).

    CAS  Article  Google Scholar 

  3. 3.

    Lipworth, L., Tarone, R. E. & McLaughlin, J. K. The epidemiology of renal cell carcinoma. J. Urol. 176, 2353–2358 (2006).

    Article  Google Scholar 

  4. 4.

    Linehan, W. M. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol. 7, 277–285 (2010).

    CAS  Article  Google Scholar 

  5. 5.

    Muller, M. et al. Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers. Clin. Genet. 92, 606–615 (2017).

    CAS  Article  Google Scholar 

  6. 6.

    Nguyen, K. A. et al. Advances in the diagnosis of hereditary kidney cancer: Initial results of a multigene panel test. Cancer. 123, 4363–4371 (2017).

    CAS  Article  Google Scholar 

  7. 7.

    Shuch, B. et al. Defining early-onset kidney cancer: Implications for germline and somatic mutation testing and clinical management. J. Clin. Oncol. 32, 431–437 (2014).

    Article  Google Scholar 

  8. 8.

    Condon, L. T., Ashman, J. N. E., Ell, S. R., Stafford, N. D., Greenman, J. & Cawkwell, L. A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas. Int. J. Cancer 100, 476–479 (2002).

    Article  Google Scholar 

  9. 9.

    Wu, J. et al. Germline mutations of renal cancer predisposition genes and clinical relevance in Chinese patients with sporadic, early-onset disease. Cancer. 125, 1060–1069 (2019).

    CAS  Article  Google Scholar 

  10. 10.

    Carlo, M. I. et al. Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma. JAMA Oncol. 4, 1228–1235 (2018).

    Article  Google Scholar 

  11. 11.

    Pritchard, C. C. et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl. J. Med. 375, 443–453 (2016).

    CAS  Article  Google Scholar 

  12. 12.

    Stuttgen, K. et al. Pathogenic germline variants in patients with metastatic breast cancer. JAMA Oncol. 5, 1506–1508 (2019).

    Article  Google Scholar 

  13. 13.

    Garcia-Donas, J. et al. Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol. 12, 1143–1150 (2011).

    CAS  Article  Google Scholar 

  14. 14.

    van der Zanden, L. F. M. et al. Description of the EuroTARGET cohort: a European collaborative project on TArgeted therapy in renal cell cancer—GEnetic- and tumor-related biomarkers for response and toxicity. Urol. Oncol. Semin. Orig. Investig. 35, 529.e9–529.e16 (2017).

    Google Scholar 

  15. 15.

    Linehan, W. M. et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N. Engl. J. Med. 374, 135–145 (2016).

    Article  Google Scholar 

  16. 16.

    Gupta, S. et al. Incidence of succinate dehydrogenase and fumarate hydratase–deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC. Hum. Pathol. 91, 114–122 (2019).

    CAS  Article  Google Scholar 

  17. 17.

    Skala, S. L., Dhanasekaran, S. M. & Mehra, R. Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC): A contemporary review and practical discussion of the differential diagnosis for HLRCC-associated renal cell carcinoma. Arch. Pathol. Lab. Med. 142, 1202–1215 (2018).

  18. 18.

    Menko, F. H. et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam. Cancer 13, 637–644 (2014).

    CAS  Article  Google Scholar 

  19. 19.

    Poulsen, M. & Bisgaard, M. MUTYH associated polyposis (MAP). Curr. Genomics 9, 420–435 (2008).

    CAS  Article  Google Scholar 

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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.

Author information




Conceptualization: M.S., C.R.-A. Data curation: M.S., J.L. Formal analysis: M.S., J.L., J.M.R.-R., E.C., C.M.-C., A.C., M.R., C.R.-A. Funding acquisition: C.R.-A. Methodology: M.S., J.L., J.M.R.-R. Resources: M.A.C., G.A., S.H., N.L., L.R., G.d.V., J.G.-D. Supervision: C.R.-A. Writing (original draft): M.S.; C.R.-A. Writing (review and editing): M.S., J.L., J.M.R.-R., E.C., C.M.-C., A.C., M.A.C., G.A., S.H., N.L., M.R., L.R., G.d.V., J.G.-D., C.R.-A.

Corresponding author

Correspondence to Cristina Rodriguez-Antona.

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Ethics Declaration

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.

Competing interests

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).

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