Germline Mutations May be Prevalent in Patients with Renal Cell Carcinoma

Renal cell carcinoma (RCC) affects approximately 64,000 patients in the United States every year; it is one of the ten most frequently diagnosed cancers nationwide. On initial diagnosis, approximately 30% of patients present with locoregional (stage III) or metastatic disease. Clear cell RCC (ccRCC) is the most common subtype of RCC and is characterized by loss of function of the von Hippel-Lindau (VHL) protein. Non-clear cell RCCs (nccRCCs) include papillary type I and II, chromophobe, microphthalmia transcription factor family translocation associated, collecting duct, medullary, and other rare subtypes.

There are several autosomal dominant inherited cancer syndromes that predispose patients to ccRCC and nccRCC, which are thought to account for 5% of all cases. However, according to Maria I. Carlo, MD, and colleagues, those estimates have been derived mainly from early-stage RCC and there have been no studies looking specifically at advanced disease.

Dr. Carlo et al. conducted a cohort study to examine the frequency of germline mutations in 76 cancer-associated genes in patients with advanced RCC. The study participants were unselected for inherited syndrome risk factors, including age at onset, multifocal disease, or family history. The researchers sought to assess the prevalence of germline mutations in known RCC predisposition genes and other cancer-associated genes and to identify clinical and pathologic factors associated with germline mutations. Results of the study were reported online in JAMA Oncology [doi:10.1001/jamaoncol.2018.1986].

The study was conducted from October 1, 2015, to July 31, 2017. The main outcomes were mutation prevalence and spectrum in patients with advanced RCC. Clinical characteristics were assessed by mutation status. Of the 267 patients with advanced (American Joint Committee on Cancer stage III or IV) RCC seen in medical oncology or urology clinics at Memorial Sloan Kettering Cancer Center were offered germline sequencing and disclosure of results.

Of the 267 patients who consented to tumor-normal testing with MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets), 95.1% (n-254) consented to receive the germline results. Of the 254, median age was 56 years, 179 (70.5%) were male and 75 (20.5%) were female, and 211 (83.1%) were non-Hispanic white.

Of the 254 patients opting to receive results, 177 had ccRCC (69.7%), 74 had nccRCC (29.1%), and three (1.2%) had both. Thirty-three patients had a history of a second malignant tumor, excluding nonmelanoma skin cancers. The most frequent secondary tumors were prostate (n=8), breast (n=4), and melanoma (n=3). Fourteen patients had bilateral or multifocal disease. and 24 reported a family history of RCC.

Forty-one patients carried pathogenic or likely pathogenic germline variants in 17 different cancer-predisposition genes. None of the cohort had more than one germline mutation. Fourteen patients carried mutations in RCC-associated genes, and 27 carried mutations in genes not clearly associated with RCC. Of the 41 patients, 17 carried mutations of high penetrance, nine of moderate penetrance, 12 of low penetrance or uncertain clinical actionability, and three in genes linked to autosomal recessive syndromes.

Of the 177 patients with ccRCC, 25 (14.1%) had a germline mutation and three in a gene associated with RCC. Among patients with nccRCC (n=74), 13 had a germline mutation, nine in a gene associated with RCC. All three of the patients with both ccRCC and nccRCC had germline mutations.

The researchers conducted analyses to assess the prevalence of mutations among patients identified as at higher risk for inherited syndromes, such as patients with a family history of RCC, early onset (defined as ≤46 years of age), and multifocal disease at diagnosis. Those with nccRCC or multifocal RCC were significantly more likely to have an RCC-associated mutation. Seven patients had germline FH mutations indicative of the hereditary syndrome HLRCC (hereditary leiomyomatosis RCC); all patients had tumors of unclassified histologic type or identified as FH deficient.

Median age at diagnosis for FH-positive patients was 49 years; four presented with metastatic disease and three later developed metastatic disease. None had multifocal RCC or a family history of RCC.

Ninety-nine patients would have met American College of Medical Genetics criteria for clinical genetics referral. Of the 14 patients with mutations associated with RCC, five would not have met referral criteria. Of the 12 patients with high or moderate penetrance mutations not related to RCC, seven would not have met referral criteria. At least six relatives of patients with mutations underwent germline testing; several were found to be carriers and were referred for discussion of dedicated cancer screening.

All but one patient had tumor sequencing data available. For the three patients with both ccRCC and nccRCC, only the ccRCC was sequenced. Of nine patients with germline CHEK2 mutations, four had loss of heterozygosity (LOH). Of the seven with germline FH mutations, five had LOH, and two had a somatic second hit.

The study limitations cited by the authors included the patients being younger and having fewer comorbid conditions than the general cancer population, and the small sample size.

“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. Phenotype-directed or tumor-only testing would have failed to identify most patients with actionable mutations. A broader approach to tumor-normal sequencing of all patients with advanced RCC, especially those with nccRCC, might help identify individual patients for whom targeted therapies are indicated, as well as family members who might benefit from preventive interventions tailored to their increased cancer risk,” the researchers said.

Takeaway Points

  1. Researchers at Memorial Sloan Kettering Cancer Center conducted a cohort study to assess the prevalence of cancer-related germline mutations in patients with advanced renal cell carcinoma (RCC).
  2. The cohort included 254 patients; of those 5.5% had mutations in syndromic RCC-associated genes, and 10.5% had mutations in other cancer-associated genes.
  3. Germline mutations may be frequent in this patient population, and genetic testing should be considered, the researchers suggest. The need for testing is particularly strong in patients with advanced non-clear cell RCC.