International Germline Susceptibility to RCC, Implications for Genetic Screening

A Merit Award-winning abstract at the 2023 International Kidney Cancer Symposium: North America offered insight into differences in global renal cell carcinoma (RCC) susceptibility and subsequent implications for genetic screening.

Kate Glennon, MD, of McGill University, showcased the first investigation into RCC susceptibility within the Canadian population. The investigation utilized targeted sequencing of 19 known RCC-related and 27 known cancer-predisposition genes.

Variations in the incidence of RCC across the world are well documented. Germline genetic variation contributes to differences in susceptibility to cancer, but genetic risk factors for RCC are poorly understood. Similarly, further research is needed to better understand differences between the genetic basis of clear cell (ccRCC) and other non-clear cell (nccRCC) disease.

Dr. Glennon and colleagues sampled a cohort of 960 Canadian patients. Along with the targeted sequencing of the 19 RCC-related and 27 cancer-predisposition genes, researchers compared potential risk-genes to those identified in other populations. They identified 39 germline pathogenic variants (PVs) in 56 patients.

Additionally, they conducted gene-based association tests between patients with RCC and noncancer controls to identify risk-genes for RCC.

Results showed that PVs in CHEK2 and ATM were significantly enriched in patients with ccRCC versus cancer-free controls. PVs in FH were enriched in patients with nccRCC. Researchers also observed an association between PVs in BRCA1/2 and ATM with the presence of metastasis.

Furthermore, gene-burden comparisons with other populations showed an enrichment for TP53 in patients with RCC from Japan, while patients with RCC from Canada, the United Kingdom, and the United States showed an enrichment for CHEK2 and ATM. Patients with RCC from the United States were enriched for germline PVs in FH and BAP1.

After evaluating the performance of current genetic screening criteria for RCC, Dr. Glennon and colleagues found that the current criteria for referral to genetic screening for hereditary RCC does not include the majority (73%) of patients harboring rare germline PVs in risk-genes for RCC.

Results of the investigation led researchers to conclude that “investigation of germline risk-genes in additional populations [is] needed to fully understand the heterogeneous susceptibility to RCC.”