Heterogeneity in germline susceptibility to renal cell carcinoma has genetic screening implications

NASHVILLE, Tenn. — An analysis of germline susceptibility to renal cell carcinoma revealed considerable heterogeneity, according to findings presented at International Kidney Cancer Symposium: North America.

The findings of the study — the first of its type performed in Canada — suggest criteria used for referral to genetic screening for hereditary renal cell carcinoma (RCC) may be inadequate, investigators concluded.

“The proportion of patients who may have a germline susceptibility to RCC did not surprise us. But when we looked further to see how many of these patients would’ve been eligible for genetic screening, it was only 30%, and that did surprise us,” researcher Kate Glennon, PhD candidate in human genetics at McGill University in Canada, told Healio. “That really highlights that we should re-evaluate the criteria that we’re using for selection of patients who are eligible for genetic screening, as well as the importance of ensuring sufficient clinicians knowledge about the clinical tests that are available.”

Although the study took place in Canada, the findings “translate pretty directly” to the United States based on the very similar ancestral backgrounds of individuals in both countries, Glennon said.

The genetic factors involved in syndromic RCC have been established, the factors that predispose an individual to sporadic disease are not well understood, Glennon said.

Syndromic cases typically are characterized by known renal cancer genes, but they only make up 5% to 8% of RCC cases, she said.

“The genetic factors that predispose for sporadic disease are just recently being studied and, rather than being limited to renal cancer genes, predisposition genes likely also include non-RCC-specific genes,” Glennon said. “Additionally, there are large unexplained variations in incidence of RCC across the globe and to further understand these differences, we need large-scale studies investigating susceptibility to RCC among different populations.”

A prior study assessed pathogenic variants in RCC among a Japanese population, with findings showing the most frequently mutated genes being TP53 in clear cell RCC and BAP1 and FH in non-clear cell RCC. A prior study of a European population showed the most frequent germline mutations were CHEK2, MITF and ATM.

“These two studies alone show the stark differences in which genes may predispose to RCC just within two populations,” Glennon said.

Glennon and colleagues aimed to assess germline susceptibility to RCC within the Canadian population. Researchers used the Ontaria Tumor Biobank to collect germline DNA from 977 patients with RCC (clear cell, n = 790; non-clear cell, 191; mixed, n = 16).

Investigators used a multiplex polymerase chain reaction (PCR)-based targeted sequencing method to identify pathogenic germline variants present in the cohort. Researchers used two panels — one targeting 27 general cancer susceptibility genes and another targeting 19 RCC-related genes.

“When it came to proportion of mutations, the frequency we observed was similar to other large studies, but the individual genes contributing to them were different,” Glennon said.

Glennon and colleagues identified 39 variants as pathogenic or loss of function, with 5.8% of patients having a germline pathogenic variant, the most frequent of which was CHEK2 c.1100delC variant (n = 11).
CHEK2 and MITF.

Among patients with clear cell carcinoma, most mutations identified were within general cancer susceptibility genes, Glennon said, Among those with the non-clear cell subtype, mutations in RCC-specific genes were observed more frequently.

Results showed an association between pathogenic variants in BRCA1/BRCA2 or ATM and presence of metastasis.

To identify risk genes for RCC within the Canadian cohort, resaerchers compared gene burden between the RCC cohort and a control data set to identify which genes showed to be significantly more mutated within the RCC cohort.

CHEK2 and ATM appeared enriched among patients with clear cell RCC, whereas pathogenic variants in FH appeared enriched among patients with non-clear cell RCC.

“These results are really similar to those seen within the European cohort, which isn’t surprising considering the largely European ancestry of the Canadian population,” Glennon said.

Glennon and colleagues also assessed differences in gene burden between published large cohorts from Canada, Europe, Japan and the United States to identify differences in risk genes between cohorts from different countries.

Results showed the cohort from Japan was enriched for pathogenic variants in TP53 (OR = 7.7; 95% CI, 2.3-39.7),whereas all others were enriched for MITF and CHEK2.

Analyses also showed patients from the United States were enriched for germline pathogenic variants in FH (OR = 11; 95% CI, 4.1-28.2) and BAP1 (OR = 8.2; 95% CI, 1.9-29).

“Unfortunately, a lack of information about ethnicity of patients didn’t allow us to report on specific population-based genetic differences; however, our findings still bring new insights into the global differences in germline susceptibility to RCC,” Glennon said. “One area we propose this is useful for is refining gene lists for clinical genetic screening for RCC based on country and population-specific data.”

For example, in Canada, guidelines for referral to genetic screening rely primarily on early age at onset, presence of bilateral or multifocal tumors, or close family history of renal cancer.

Based on those criteria, 41 (73%) of the 56 Canadian patients found to have germline pathogenic variants would not have been eligible for genetic screening. Similar rates have been reported in the United States and United Kingdom, Glennon said.

The findings highlight the need to revise criteria to capture more patients affected by potentially actionable germline mutations. In addition, the results suggest it may be necessary to expand the list of genes for screening , Glennon said, noting that BRCA1, BRCA2, CHEK2 and ATM typically are not included in genetic screening for renal cancer in Canada.