medwireNews: Germline mutations may be common in patients with advanced renal cell carcinoma (RCC) and may have the potential to guide therapy if detected, US researchers report.
However, “[p]henotype-directed or tumor-only testing would have failed to identify most patients with actionable mutations,” Maria Carlo and colleagues from the Memorial Sloan Kettering Cancer Center in New York write in JAMA Oncology.
They add: “A broader approach to tumor-normal sequencing of all patients with advanced RCC, especially those with [non-clear cell] RCC, might help identify individual patients for whom targeted therapies are indicated, as well as family members who may benefit from preventive interventions tailored to their increased cancer risk.”
The researchers carried out germline sequencing of 76 cancer-related genes in paired normal and tumor DNA samples from 254 patients (median age, 56 years; 70.5% men; 83.1% non-Hispanic white) with stage III or IV RCC.
In total, 41 (16.1%) patients carried pathogenic or likely pathogenic germline variants in 17 different cancer-predisposition genes.
The majority (10.5%) of pathogenic variants were detected in genes not typically associated with RCC, such as checkpoint kinase 2 (CHEK2; 3.5%), which is involved in the DNA damage response and occurred at a rate threefold higher than that expected in the general population.
The remaining 5.5% of detected variants occurred in RCC-associated genes, most commonly fumarate hydrase (FH; 2.8%).
Interestingly, all of the mutations in FH occurred among the 74 patients with non-clear cell RCC. And these patients were significantly more likely to have an RCC-associated gene mutation than the 177 patients with clear cell RCC, at rates of 11.7% and 1.7%, respectively.
Overall, 21% of patients with non-clear cell RCC had germline mutations and, according to the researchers, half of these were in a gene that could be used to guide therapy.
Of note, more than an third (35.7%) of patients with mutations in RCC-associated genes did not meet current clinical guidelines for genetic testing.
Patrick Pilié (University of Texas MD Anderson Cancer Center, Houston, USA) and Kathleen Cooney (University of Utah, Salt Lake City, USA) write in an accompanying commentary that this particular finding highlights the importance of the study and “necessitates a rethinking of guidelines because not only the patient but potentially generations of family members are affected if these mutations go undetected.”
They add that the data support “the mounting evidence that populations with advanced cancer harbor higher rates of pathogenic germline variants” with the potential to be “important as biomarkers for an array of targeted and immune-based anticancer therapies.”
Pilié and Cooney conclude: “In the modern era of oncology with near-ubiquitous sequencing of tumor DNA, increasing numbers of germline variants in cancer-related genes may be found, and a collaborative team-based approach that incorporates genetic counseling with treatment planning and cancer prevention is needed to ethically and appropriately interpret these genetic findings in the context of patient care.”
By Laura Cowen
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