Germline mutations in cancer-associated genes in patients with advanced renal cell carcinoma (RCC) are more prevalent than previously reported.
In addition, at least one third of patients harboring these mutations do not meet current referral criteria for genetic testing, but they and their families could benefit from such an approach, the researchers suggest.
The findings come from a single-institution study reported by Maria Carlo, MD, Memorial Sloan Kettering Cancer Center, New York City, and colleagues.
The team found that 16.1% of 254 patients with advanced RCC carried a pathogenic germline mutation, 5.5% of them in RCC-associated genes and 10.5% of them in non–RCC-associated genes.
Moreover, 20% of patients with non–clear cell RCC (nccRCC) carried a germline mutation, approximately half of which had the potential to direct therapy decisions.
The study was published online July 5 in JAMA Oncology.
"These novel findings suggest that patients with advanced nccRCC regardless of family history warrant referral to a cancer geneticist to consider germline genetic testing and that this testing should include RCC genes and consideration of a broader set of genes," comment Patrick Pilié, MD, University of Texas MD Anderson Cancer Center, Houston, and Kathleen Cooney, MD, Huntsman Cancer Institute, University of Utah, Salt Lake City, in a related editorial.
"The fact that more than 30% of patients with pathogenic mutations in canonical RCC genes did not meet current criteria for genetic testing necessitates a rethinking of guidelines because not only the patient but potentially generations of family members are affected if these mutations go undetected," they write.
The analysis involved paired tumor and normal DNA sequencing of 76 cancer-related genes in 254 patients with stage III and IV RCC. Patients were unselected for inherited syndrome risk factors, including age at onset, multifocal disease, or family history, the authors point out.
The median patient age was 56 years. Over 70% of patients were male, and over 83% were non-Hispanic white.
"Tumor and blood samples from patients were sequenced using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a next-generation sequencing assay," the investigators explain.
Most of the group had clear cell RCC, the most common subtype of kidney cancer. In this large subgroup of patients, 14.1% had a germline mutation and another 1.7% had a mutation in an RCC-associated gene.
In patients with nccRCC, 17.5% carried a germline mutation, 12.2% of them in an RCC-associated gene.
"For genes not traditionally associated with RCC, we compared mutation frequencies with those in the general population," the investigators write.
Among this group of mutations, the odds of patients with RCC harboring a mutation exceeded those in the general population only in the prevalence of CHEK2: Patients with renal cancer had a threefold higher risk of carrying the CHEK2 mutation relative to the general population, at an odds ratio of 3.0 (P = .003).
As the researchers note, germline CHEK2 mutations are associated with an increased risk for several cancers and not just RCC.
ACMG Criteria for Referral
In the overall cohort, 39% of patients would have met current American College of Medical Genetics and Genomics (ACMG) criteria for genetics referral.
However, over one third of patients with RCC-associated mutations — 35.7% — would not have qualified for referral, the authors point out, including three patients carrying the fumarate hydrase (FH) mutation.
They also note that any relative who is found to carry the FH mutation should be considered for screening because early detection of cancer may enhance the likelihood of cure if they develop RCC.
"We found that despite almost 40% of patients in this cohort meeting the broad guideline criteria, 36% of patients with high-penetrance RCC-associated mutations would have been missed," Carlo and colleagues observe.
"With potentially increasing numbers of mutations identified in patients and relatives, optimal cancer screening schedules need to be studied," they write.
Commenting further on the findings, the editorialists point out that the most commonly mutated gene in patients with nccRCC in the current study was the FH mutation, which is associated with a syndrome known as hereditary leiomyomatosis and renal cell cancer (HLRCC).
"It is imperative to identify patients with germline mutations in FH and HLRCC syndrome because bevacizumab plus either erlotinib or everolimus were recently added to the National Comprehensive Cancer Network guidelines as recommended treatments for HLRCC-associated papillary RCC," Pilié and Cooney note.
They also point out that "histologic findings matter" in that patients with either nccRCC or multifocal disease or both were much more likely to harbor mutations.
"This study contributes to the mounting evidence that populations with advanced cancer harbor higher rates of pathogenic germline variants," Pilié and Cooney state.
"These germline mutations not only inform cancer risk for the patient and family but are also important as biomarkers for an array of targeted and immune-based anticancer therapies," they add. "[A]ll patients with advanced nccRCC warrant referral to genetic counseling to consider germline testing."
Carlo reports serving as a consultant or in an advisory role for Pfizer. Other coinvestigators reported multiple relationships with industry, which are listed in the publication. Pilié and Cooney have disclosed no relevant financial relationships.
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Cite this: Patients With Renal Cancer Could Benefit From Genetic Testing - Medscape - Jul 11, 2018.