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Germline mutations common in advanced renal cell carcinoma

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July 5, 2018

A substantial proportion of patients with advanced renal cell carcinoma harbored germline mutations, many of whom were not eligible for genetic testing under current criteria, study data showed.

“Inherited renal cell carcinoma syndromes are thought to account for 5% of all cases; however, these estimates were derived from mostly early-stage renal cell carcinoma, and no studies have specifically looked at advanced disease,” Maria I. Carlo, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “Recent studies suggest that germline mutations may be more frequent in patients with advanced cancer compared with those with early-stage disease.”

Identifying inherited mutations can be helpful to guide systemic therapy or clinical trial eligibility — especially in the case of FH and MET mutations — and provide family members with cancer risk information to promote early detection. However, uncertainty exists as to which patients with renal cell carcinoma should be referred for genetic testing.

Carlo and colleagues examined the prevalence of germline mutations in 76 known renal cell carcinoma predisposition genes and other cancer-associated genes, and they sought to identify clinical and pathologic factors associated with germline mutations.

The analysis included 254 patients (median age, 56 years; 70.5% men; 83.1% white) with advanced renal cell carcinoma who underwent germline sequencing.

Forty-one patients (16.1%) harbored a pathogenic or possibly pathogenic germline mutation in 17 genes associated with a predisposition to cancer.

Fourteen patients (5.5%) carried mutations in genes associated with syndromic renal cell carcinoma — seven in FH; three in BAP1; and one each in VHL, MET, SDHA and SDHB.

CHEK2 (n = 9) and FH (n = 7) were the most frequent mutations.

Among genes that had not been previously associated with renal cell carcinoma, CHEK2 appeared “overrepresented” among patients with the disease compared with the general population (OR = 3; 95% CI, 1.3-5.8), the researchers wrote.

Researchers observed a germline mutation in 25 of 177 (14.1%) patients with clear cell renal cell carcinoma and 13 of 74 (17.5%) patients with non-clear cell renal cell carcinoma. Patients with non-clear cell disease appeared significantly more likely to have a mutation associated with renal cell carcinoma (11.7% vs. 1.7%; P = .001).

Eight patients (10%) with non-clear cell renal cell carcinoma had a mutation in a gene that could help guide cancer therapy.

Five patients (35.7%) with renal cell carcinoma-associated mutations did not meet the clinical guidelines for genetic testing.


“Phenotype-directed or tumor-only testing would have failed to identify most patients with actionable mutations,” Carlo and colleagues wrote. “A broader approach to tumor-normal sequencing of all patients with advanced renal cell carcinoma, especially those with non-clear cell renal cell carcinoma, 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.”

These findings add to the evidence that pathogenic germline variants occur more frequently among patients with advanced cancer, Patrick G. Pilié, MD, physician in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, and Kathleen A. Cooney, MD, MACP, professor and chair of the department of internal medicine at The University of Utah, wrote in a related editorial.

“These germline mutations not only inform cancer risk for the patient and family, but [also are] important as biomarkers for an array of targeted and immune-based anticancer therapies,” they wrote. “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 Andy Polhamus

Disclosures: Carlo reports a consultant/advisory role with Pfizer. Please see the study for all other authors’ relevant financial disclosures. Cooney and Pilié report no relevant financial disclosures.

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All cancers are believed to have a genetic basis. Specifically, a mutation acquired in a particular cell’s DNA — which may be due to environmental causes — permits unregulated growth. These mutations are limited to the cell of origin in a particular organ and are termed somatic mutations. Somatic mutations are therefore detected by evaluation of the tumor.

Fewer cancers are believed to be hereditary, meaning that the mutation is inherited and therefore affects all the cells in the body — termed germline mutations. These mutations are often detected in the blood and can be passed from parent to offspring. Inherited mutations are believed to cause cancers at an earlier age and are often multiple and may be more aggressive. 

The genetic mutations involved in kidney cancer are among the best known and have led to multiple new therapies over the last decade that have nearly tripled OS for patients with advanced disease. 

Current national guidelines recommend genetic testing for kidney cancer only under specific circumstances, such as age of about 46 years or younger, with the goal of identifying mutations that improve screening of family members and/or direct physicians to more appropriate therapies for a given patient.

Investigators in this study evaluated 254 patients with advanced kidney cancer for 76 cancer-associated genes. Germline mutations occurred among 16% of patients, of which 10.5% were in genes not known to be associated with kidney cancer — but were known to be associated with other cancer types — and 5.5% had mutations in known kidney cancer-associated genes.  Germline mutations were even more common (20%) in patients with the less common types of kidney cancer, non-clear cell. 

These data have several clinical implications. They suggest that, in patients with advanced kidney cancer, germline mutations in cancer-associated genes are more prevalent than previously thought. This information may help guide therapy and counseling/screening of family members.  Moreover, as our understanding of actionable and targetable mutations grows, patients with advanced cancers might benefit from genetic screening, even if they don’t meet existing established guidelines for genetic testing. 


Robert G. Uzzo, MD


Fox Chase Cancer Center

Disclosure: Uzzo reports no relevant financial disclosures.