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.
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. .