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More Kidney Cancer Patients Have Hereditary Mutations Than Previously Thought

NEW YORK (GenomeWeb) – Patients with advanced kidney cancer have germline mutations in hereditary cancer-associated genes at higher frequencies than previously thought, including in genes related to kidney and other cancers, according to research done at Memorial Sloan Kettering Cancer Center.

In a study published yesterday in JAMA Oncology, the MSKCC researchers sequenced germline DNA of 254 patients with advanced renal cell carcinoma to evaluate the prevalence of germline mutations in that patient cohort.

Overall, around 16 percent of patients had germline variants, and for those with non-clear cell renal carcinoma, 20 percent had a germline mutation, about half of which were therapeutically relevant.

"Our results suggest that germline mutations in cancer-associated genes in patients with advanced RCC may be prevalent, and many of these mutations can be used to guide therapy," the authors wrote.

Previous research has indicated that inherited forms of renal cell carcinoma account for around 5 percent of cases, but that estimate was derived primarily from early-stage disease. More recent research has suggested that the prevalence of inherited mutations may be higher among patients with advanced disease.

For their study the MSKCC researchers recruited patients with advanced renal cell carcinoma, offering them germline sequencing and disclosure of results for 76 genes associated with hereditary cancer. The investigators used their internally developed next-generation sequencing assay, MSK-IMPACT, to analyze the patients and then further focused on germline variants in 76 genes.

Of the 254 patients, 177 had clear cell RCC while 74 had non-clear cell RCC, and three patients had both.  Of those, 24 patients had a family history of RCC.

The researchers found that 41 patients, or 16 percent, had pathogenic germline variants in 17 cancer predisposition genes. Twenty-seven, or nearly 11 percent, of those patients had mutations in genes not associated with RCC, while just over 5 percent of patients had mutations in RCC-associated genes.

Of the 14 patients with RCC-associated mutations, five, or 36 percent, would not have met criteria for genetic testing. And, of 12 patients with high- or moderate-penetrance genes that were not associated with RCC — including mutations to CHEK2, ATM, PALB2, and BRCA2, MSH6, and RAD51C — seven would not have met referral criteria.

Around 9 percent of patients with advanced non-clear cell RCC had a mutation in the FH gene, conferring diagnosis of hereditary leiomyomatosis, an autosomal dominant inherited syndrome associated with RCC and uterine and cutaneous leiomyomas. The patients with these mutations would have been difficult to identify by clinical criteria, since none had a family history of RCC nor did oncologists identify any cutaneous lesions that are often associated with the syndrome.

The researchers also identified a number of germline mutations that would be relevant for treatment or clinical trial enrollment. In 10 percent of patients with non-clear cell RCC, they found predictive mutations that would not have been identified with tumor-only sequencing.

Overall, although there are broad guidelines that indicate eligibility for genetic counseling for patients with RCC, including age at diagnosis, family history, and histologic guidelines that 40 percent of the entire cohort met, 36 percent of patients in the cohort who had high-penetrance RCC-associated variants would nonetheless have been missed.

In a related editorial in JAMA Oncology, Kathleen Cooney from the University of Utah and Patrick Pilié at the University of Texas MD Anderson Cancer Center wrote that the researchers' findings that most pathogenic variants were in genes not typically associated with RCC, highlights the "concept that broader panel testing may be warranted in select patients with RCC." And, because non-clear cell RCC subtypes were disproportionally enriched for germline variants at around 21 percent, and had a higher rate of variants in RCC-related genes, the results suggest that "all patients with advanced non-clear cell RCC warrant referral to genetic counseling to consider germline testing."