Germline Variants in Renal Cell Carcinoma Patients - Expert Commentary

Renal cell carcinoma (RCC) accounts for approximately 2% of all cancers. The predisposing risk factors for RCC are still not well-defined. Understanding germline genetic predisposition for RCC in different ethnic groups is an area of unmet need.

A new study published by Abou Alaiwi et al. in Cell Reports investigated the prevalence of germline candidate risk variants among 1,829 RCC patients. The majority of patients had clear cell RCC (ccRCC) (35.9%). Other histologies were represented, including non-clear cell RCC (nccRCC), papillary RCC, and chromophobe RCC. The mean age at diagnosis was 51 years. Most of the patients were white (69%), and 99 (5.4%) were African Americans. Out of 1713 patients, 315 had a positive family history of RCC in first- or second-degree relatives. The authors used two methods to assign the ancestry: the self-reported ancestry and the ancestry index. The ancestry index is a quantitative index of genetic ancestry derived from principal component analysis.

The frequency of patients with pathogenic or likely pathogenic (P/LP) germline variants was 17%. The top recurrent variants were loss-of-function (LOF) variants in CHEK2 (2.4%). The authors conducted a correlative analysis of the most commonly affected six genes [LOF CHEK2, FH, MUTYH, BRCA2, ATM, and FLCN] with clinical variables. Logistic regression was performed to evaluate the association between P/LP germline variants and the ancestry index. The analysis revealed that the presence of CHEK2 germline variants was associated with a lower African ancestry index score (p = 0.017). In contrast, P/LP germline variants in FH were associated with a higher African ancestry index (p = 0.014). Similarly, self-reported ancestry showed a trend toward the enrichment of variants in FH in African American patients compared to white patients (3.3% versus 1%, p = 0.08), and the reverse was true for LOF variants in CHEK2 (0%, versus 2.7%, p = 0.21).

The investigators analyzed the association between histology and germline variants in the previously mentioned six genes. P/LP variants in FLCN were significantly more frequent in patients with non-ccRCC compared to ccRCC (odds ratio [OR] = 6.0; confidence interval [CI] = 1.8–20.9; p < 0.006). Similarly, the frequency of FH P/LP variants was significantly higher in non-ccRCC patients compared to ccRCC (OR = 23.1; CI = 4–251.7; p < 0.0001). Enrichment analysis showed that CHEK2 and FH variants rates in the White and African American subpopulations in the RCC cohort were significantly higher than ethnicity-matched gnomAD subpopulations.

The investigators found that the frequency of high, moderate, and low penetrance variants was 8.1%, 5.3%, and 3.1%, respectively. Actionable P/LP variants were detected in 10.3% of RCC patients. Using self-reported ancestries, the frequency of actionable variants was lower in African Americans compared to white patients (African Americans, 1%; White, 11.4%).

This study presents evidence that specific germline variants have different distributions in patients from different ethnicities. These data provide an important first step towards designing more effective personalized screening and preventive strategies.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


  1. Abou Alaiwi S, Nassar AH, Adib E, Groha SM, Akl EW, McGregor BA, et al. Trans-ethnic variation in germline variants of patients with renal cell carcinoma. Cell Rep. 2021;34(13):108926. PMID: 33789101
  2. Carlo MI, Mukherjee S, Mandelker D, Vijai J, Kemel Y, Zhang L, et al. Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma. JAMA Oncol. 2018 Sep 1;4(9):1228. PMID: 29978187

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