The study fills the knowledge gaps related to germline mutations in early-onset RCC


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

Overall, inherited renal cell carcinoma syndromes have been linked to approximately 5% -8% of kidney cancers. A previous analysis2 determined that an age limit of ≤46 years offered the optimal combination of specificity and sensitivity for identifying hereditary RCC. Consequently, genetic counseling is recommended by the NCCN and AUA guidelines for patients with RCC aged 46 years or younger.

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 usefulness 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 tumor germline sequencing between different tumor types. Patients had next-generation sequencing of a panel of more than 77 cancer predisposition genes, regardless of the patient’s individual or family history. The second group of patients came from the Clinical Genetic Service (68 patients), which performs mono or multigen tests guided by the 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 renal tumors. A family history of RCC was reported for 35 (15%) patients and 22 (9%) patients had syndromic histology.

Patients in both protocols received pre-test 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 evaluation consisted of a detailed review of the patient’s personal history, three-generation pedigree, and tumor histology.

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

Genes associated with RCC syndromes include VHL (from 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) e CDC73 (hyperparathyroidism-tumor of the jaw syndrome).

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

Researchers evaluated the clinicopathological factors associated with mutations in the RCC gene. Syndromic histology (P. <.001) and syndromic characteristics (P. <.001) were significantly associated with mutations in the RCC gene. Thirteen and 12 of the 21 patients with RCC-associated gene mutations had syndromic histology and syndromic features, respectively.

Family history per se 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 mutations in the RCC gene (P. <.001).

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

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

In his concluding remarks, Truong said that the RCC genetic panel test is “most useful” in patients with 1 or more of these clinicopathological factors. He 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. Annual meeting of the Society of Urological Oncology 2020 (virtual). 3-5 December 2020.

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


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