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Renal Cell Carcinoma Risk Gene Representation Can Vary With Ancestry

NEW YORK – The genetic predisposition to renal cell carcinoma (RCC) appears to vary in individuals from other ancestral backgrounds, new research suggests.

Using targeted germline sequence data for more than 1,800 individuals with one or more RCC tumors, the researchers searched for pathogenic or likely pathogenic risk variants with ties to RCC, identifying such variants in RCC-related genes in some 17 percent of those tested. While more than 10 percent of participants carried clinically actionable variants, they noted, the distribution of those variants within the FH and CHEK2 genes appeared to differ somewhat depending on individuals' ancestry.

Although many of the past studies looking at inherited risk of RCC have been done in individuals of European descent, the team noted, the current findings suggested that the presence of pathogenic or likely pathogenic variants in the FH gene tended to increase alongside African ancestry. In contrast, risky CHEK2 germline variants more often turned up in individuals from those with non-Finnish European ancestry.

"This work helps understand the underlying biological differences in RCC between Africans and non-Africans, and paves the way to more comprehensive genomic characterization of under-represented populations," senior and corresponding author Toni Choueiri, a genitourinary oncology researcher at the Dana-Farber Cancer Institute, and his colleagues wrote in Cell Reports on Tuesday.

For their analyses, the investigators tapped into clinical germline sequence data for 1,829 individuals with RCC who underwent panel testing on one to more than 100 genes at Invitae from early 2017 to the fall of 2019.

Based on self-reported ancestry, the cohort encompassed nearly 1,300 Caucasian individuals, 94 with Ashkenazi Jewish ancestry, 55 Asian or Pacific Islanders, 99 African Americans, and more than 100 Hispanic individuals, though the team also tapped into participants' common SNP profiles and available computational tools to estimate ancestry tracts.

From the germline sequence data, the researchers unearthed pathogenic or likely pathogenic variants in 17 percent of those profiled, particularly in the CHEK2, MUTYH, FH, BRCA2, and ATM genes. Just over 5 percent of participants carried risky variants in one of 12 genes implicated in RCC risk in the past, they noted, including half a dozen genes with sufficient data to search for ancestry correlations.

The latter analysis highlighted lower-than-usual levels of loss-of-function germline mutations in the CHEK2 gene in individuals with more African ancestry, which appeared to coincide with an uptick in ancestry-specific FH gene variants. European ancestry showed the opposite pattern, despite similar rates of overall variation in the CHEK2 and FH genes in population data housed in the gnomAD database.

The authors cautioned that "when variants ascertained in European populations are assessed, this can falsely lead to the conclusion that these populations harbor more variants than do patients of African descent, and as such should be interpreted more cautiously."

"Several genes with potential [pathogenic or likely pathogenic] variant enrichment in different ancestries were identified," they wrote, "and will require future large-scale studies with more non-white representation to confirm these findings."