Study fills in knowledge gaps related to germline mutations in early-onset RCC

Researchers examined the prevalence of germline mutations, as well as clinicopathologic factors linked to an increased risk of carrying these mutations.

At the 2020 Society of Urologic Oncology Annual Meeting, Hong Truong, MD, shared findings from a study analyzing the prevalence of germline mutations associated with early-onset renal cell carcinoma (RCC), as well as clinicopathologic factors linked to an increased risk of carrying these mutations.1

Overall, hereditary RCC syndromes have been linked to approximately 5% to 8% of kidney cancers. A prior analysis2 determined that an age cutoff of ≤46 years offered the optimal combination of specificity and sensitivity for identifying hereditary RCC. Accordingly, genetic counseling is recommended by the NCCN and AUA guidelines for patients with RCC aged 46 years and under.

Despite these developments, Truong, of Memorial Sloan Kettering Cancer Center, said significant knowledge gaps still exist. “The prevalence and spectrum of germline mutations implicated in early-onset RCC is still unknown,” said Truong, adding that, “The utility of age of onset alone in predicting the presence of germline mutation is unknown.”

The overall study cohort pooled 233 patients with RCC aged ≤46 years from 2 institutional protocols. The first was the MSK-IMPACT protocol (165 patients) which conducts prospective matched tumor germline sequencing across different tumor types. The patients had next-generation sequencing of a panel of more than 77 cancer predisposition genes, irrespective of a patient’s individual history or family history. The second group of patients were from Clinical Genetic Service (68 patients), which performs single or multigene testing guided by a patient’s personal and family history.

Across the overall study population, the median age at initial diagnosis was 38 years (range, 21-46), seventy-four percent of patients were white, 8% were Black, 6% were Asian, and 11% were other/unknown race. Thirty-five (15%) patients had syndromic features and 21 (9%) patients had bilateral/multifocal kidney tumors. A family history of RCC was reported for 35 (15%) patients and 22 (9%) patients had syndromic histology.

Patients from both protocols received pre-testing genetic counseling, as well as additional counseling for those patients who tested positive for a germline mutation. A genetic risk assessment was conducted for all patients. The assessment consisted of a detailed review of a patient’s personal history, three-generation pedigree, and tumor histology.

“Only pathogenic or likely pathogenic variants were considered positive germline mutations,” said Truong.

Genes associated with RCC syndromes include VHL (von Hippel-Lindau syndrome), MET (hereditary papillary RCC), FH (hereditary leiomyomatosis and RCC), TSC1/2 (tuberous sclerosis complex), FLCN (Birt-Hogg-Dube syndrome), SDHA/B/C/D (hereditary pheochromocytoma and paraganglioma), PTEN (Cowden syndrome), BAP1 (BAP1 tumor predisposition syndrome), MITF (MITF cancer syndrome), and CDC73 (hyperparathyroidism-jaw tumor syndrome).

Overall, 21 (9%) patients had RCC-associated genes, including FH (n = 12), VHL (n = 4), SDHB (n = 2), BAP1 (n = 1), TSC1 (n = 1), and FLCN (n = 1). Another 21 (9%) patients had mutations in non-RCC genes. These non-RCC genes included TP53, ATM, BRCA1, CHEK2, RET, PALB2, BARD1, APC, MUTYH, FANCC, RAD50, RECQL, and RECQL4.

The researchers assessed clinicopathologic factors associated with RCC gene mutations. Syndromic histology (P <.001) and syndromic features (P <.001) were significantly associated with RCC gene mutations. Thirteen and 12 of the 21 patients with RCC-associated gene mutations had syndromic histology and syndromic features, respectively.

Family history by itself was not significantly associated with RCC gene mutations in the study cohort; however, the combination of the 3 phenotypic markers of syndromic histology, syndromic features, and family history showed a strong association with RCC gene mutations (P <.001).

Non-clear cell histology is not a typical phenotypic marker of hereditary RCC; however, in the study, it was strongly associated with RCC mutations (P = .003).

Truong said that an analysis using the 4 clinicopathologic factors analyzed in the study—syndromic histology, syndromic features, family history, and non-clear cell histology—would identify all 21 patients with RCC gene mutations (P <.001).

In her concluding remarks, Truong said that RCC gene panel testing has the “highest utility” in patients with 1 or more of these clinicopathologic factors. She added that, “In the absence of other phenotypic markers of RCC syndromes, early age of onset offers limited incremental utility in identifying patients with hereditary RCC.”


1. Truong H, Sheikh R, Kotecha R, et al. Prevalence of germline mutations in cancer susceptibility genes in patients with early onset renal cell carcinoma. 2020 Society of Urologic Oncology Annual Meeting (virtual). December 3-5, 2020.

2. Shuch B, Vourganti S, Ricketts CJ, et al. Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol. 2014;32(5):431-437. doi: 10.1200/JCO.2013.50.8192