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ESHG: UK Study Finds 6 Percent of Renal Cell Carcinoma Patients Carry Cancer Risk Variant

VIENNA – About 6 percent of renal cell carcinoma (RCC) patients carry a germline cancer risk variant, including in genes not previously associated with the disease, according to a new study by researchers in the UK, suggesting that additional genes should be included in panels for RCC patients and that more patients should be tested.

In a talk at the European Society of Human Genetics annual meeting in Vienna on Saturday, Bryndis Yngvadottir, a researcher at the University of Cambridge, presented results from the recently published study, which looked at data from RCC cases in the UK 100,000 Genomes Project.

RCC, which affects the lining of tubules in the kidney, is the most common type of kidney cancer, which is diagnosed in about 431,000 individuals worldwide each year, with more than 179,000 annual deaths. While it often occurs in patients with certain cancer predisposition syndromes, where the age of onset is usually early, most cases are sporadic. About 2 to 3 percent of RCC patients have a family history of the disease, but it has been unclear so far what percentage of RCC patients carry a pathogenic germline variant.

To find out, Yngvadottir and her colleagues analyzed germline whole-genome sequencing data for 1,336 RCC patients, who were not selected for having a family history of the disease or an inherited cancer syndrome, and searched for rare, damaging single nucleotide variants, indels, or structural variants in 121 cancer susceptibility genes, of which 18 had been previously associated with RCC.

They found that 6.4 percent of patients had at least one pathogenic or likely pathogenic variant, a total of 88. Of those, 68 percent mapped to genes that had previously been associated with RCC — most often CHEK2 — and 32 percent to cancer risk genes that had not been linked with RCC before, most often ATM.

Interestingly, only four of the RCC-associated genes where variants were detected are currently routinely tested in the UK in RCC patients suspected of familial cancer, Yngvadottir noted. Also, because the age cutoff for such testing in the UK is currently 46 years, several RCC patients who did have a cancer risk variant would have been missed under the current guidelines.

In addition, the researchers found 64 variants of unknown significance in the genes they tested, of which they classified 24 as "hot VUSs," meaning those are likely to be pathogenic but require further validation studies.

They did not find any association between patients who had a cancer risk variant and their gender, age, cancer histology, or tumor stage. Yngvadottir also said they have not looked at correlations between germline variants and treatment response or overall survival yet.

As a result of their findings, the number of genes RCC patients are tested for in the UK should be expanded, she said, in particular to include CHEK2 and all subunits of SDHx, and the age for testing eligibility should be increased from 46 years to 50 years in order to catch more patients who carry a germline risk variant.