From the Journals

Many actionable mutations may be missed in current testing of advanced RCC

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Consider expanded germline testing in the context of interdisciplinary care

In the present study, the number of patients who did not meet current criteria for genetic testing, but who had germline RCC-associated mutations, should prompt reevaluation of testing criteria for individuals with advanced RCC.

Particularly for patients with advanced nccRCC, a genetic referral should be considered to weigh germline testing as well as testing for an expanded set of mutations. Patients with advanced ccRCC may also benefit from a broader testing panel that may include some non-RCC related genes.

Further research is needed to elucidate the genotype-phenotype association in some of the non-RCC mutations seen in this cohort, particularly in CHEK2 mutations. There are currently no screening guidelines for CHEK2 in regard to RCC, and the risk for RCC among those with these mutations is not known. RCC patients who have biallelic loss of DNA damage repair genes such as CHEK2 may benefit from treatment that targets these pathways, though these therapies are not currently offered for RCC.

The study population were individuals with advanced RCC, and the increased numbers of pathogenic germline mutations seen in this population are consistent with other studies finding higher rates of these mutations in patients who have other cancer with advanced disease. As this body of knowledge accumulates, interdisciplinary teams will be able to give more accurate information about risk and prognosis to patients and families and, increasingly, offer optimized care.

Dr. Patrick Pilié is an oncologist at the University of Texas MD Anderson Cancer Center, Houston; Dr. Kathleen Cooney is chair of the department of internal medicine and H.A. and Edna Benning Presidential Endowed Chair at the University of Utah, Salt Lake City. These remarks are drawn from a jointly authored editorial accompanying the study’s publication.



Germline mutations in patients with advanced renal cell carcinoma may be more common than previously suspected.

In a single-center cohort of 254 patients with advanced renal cell carcinoma (RCC) who received matched tumor-germline DNA sequencing, over a third (35.7%) of patients who had mutations in genes associated with RCC had not met current clinical criteria for testing.

In all, pathogenic germline mutations were identified in 41 patients (16.1%), with 14 patients’ mutations (5.5%) in genes known to be associated with RCC. For the remaining 27 patients (10.5%), the mutations were in non–RCC-associated genes, investigators reported in JAMA Oncology.

Of the non–RCC-associated mutations, CHEK2 was particularly common among patients with clear cell RCC (ccRCC), occurring in eight patients with ccRCC and two with non ccRCC (nccRCC). The overall odds ratio for this mutation among the study cohort was 3.0, compared with the general population (95% confidence interval 1.3-5.8; P = .003). “Although there are currently no RCC-specific screening recommendations for individuals with CHEK2 mutations, there may be incremental screening for other cancers, justifying including this gene on RCC panel tests,” wrote Maria Carlo, MD, and her coauthors.

Germline FH mutations were seen in seven patients, all with nccRCC. This higher rate of hereditary leiomyomatosis and RCC (HLRCC) was higher than previously reported in the literature, and clinical cues to the diagnosis were few among the study patients. Even though clues pointing to HLRCC were seen when tumor samples were submitted for histopathology to the genitourinary specialists at the study site, “it is unclear whether nonspecialist pathologists would be able to draw the same conclusions,” wrote Dr. Carlo and her colleagues.

Renal cell cancer–associated mutations were significantly more common in patients with nccRCC than in the ccRCC group: 9/74 (11.7%) nccRCC patients had an RCC-associated mutation, compared with 3/177 of the ccRCC group (P = .001).

The patient’s course of therapy could be guided by the mutation identified in 10% (eight) of the nccRCC patients, “none of which would have been identified with somatic-only sequencing,” wrote Dr. Carlo and associates. “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 254 patients (median age 56 years, 70.5% male, 83.1% non-Hispanic white) were drawn from 267 patients with American Joint Committee on Cancer (AJCC) stage III or IV RCC participating in clinical trials at Memorial Sloan Kettering Cancer Center, New York, where Dr. Carlo practices as an oncologist. The patients included in the cohort were those who consented to germline sequencing and results disclosure.

To determine which pathogenic variants were identified by the study protocol that would have been missed by current testing standards, the investigators assumed that for those who met guidelines, the multigene test panel would probe for VHL, VH, FLCN, MET, SDHB, SDHD, BAP1, TSC1, TSC2, TP53, and MITF. If another mutation was picked up by the next-generation sequencing used in the study, or if a mutation was found in an individual who otherwise would not have been tested, the finding was considered incremental and attributable to the study protocol.

Implications of the additional mutations picked up by the tumor-germline sequencing approach go beyond the patient, said the researchers, who have seen several of the study participants’ family members receive positive test results for cancer-associated mutations as well. “Relatives who are also found to carry FH mutations should be considered for RCC screening. Early detection may increase the likelihood of cure and survivorship,” wrote Dr. Carlo and her coinvestigators.

Dr. Carlo reported serving as a consultant for Pfizer. Other authors reported multiple associations with pharmaceutical companies. The study was funded by the National Institutes of Health, the J. Randall and Kathleen L. MacDonald Kidney Cancer Research Fund, and the Robert and Kate Niehaus Center for Inherited Cancer Genomics at Memorial Sloan Kettering Cancer Center.

SOURCE: Carlo M et al. JAMA Oncol. 2018 Jul 5. doi: 10.1001/jamaoncol.2018.1986.

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