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Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma


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Maria I. Carlo, MD

Maria I. Carlo, MD

In a study reported in JAMA Oncology, Maria I. Carlo, MD, of the Department of Medicine, Memorial Sloan Kettering Cancer, and colleagues found a high prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma (RCC).

In this cohort study, conducted between October 2015 and July 2017, 254 of 267 patients with advanced (stage III or IV) RCC seen in medical oncology or urology clinics at Memorial Sloan Kettering Cancer Center underwent germline sequencing under an institutional protocol of matched tumor-germline DNA sequencing. Among the 254 patients, 177 had clear cell RCC (69.7%), 74 had non–clear cell RCC (29.1%), and 3 (1.2%) had both.

Prevalence of Mutations

Germline cancer-associated mutations were identified in 41 patients overall (16.1%), with 14 (5.5%) having mutations in syndromic RCC-associated genes (7 in FH, 3 in BAP1, and 1 each in VHL, MET, SDHA, and SDHB) and 27 (10.6%) having other cancer-associated mutations. The most common mutations were CHEK2 (n = 9) and FH (n = 7). Of genes not previously associated with RCC, CHEK2 was significantly more prevalent in patients with RCC vs the general population (odds ratio = 3.0, P = .003).

Among 74 patients with non–clear cell RCC, 13 (17.5%) had a germline mutation, with 9 (12.2%) having mutation in an RCC-associated gene. Among the 3 patients with both clear cell RCC and non–clear cell RCC, all had germline mutations, 2 in BAP1 and 1 in CHEK2. Patients with non–clear cell RCC were significantly more likely to have an RCC-associated gene mutation vs those with clear cell RCC (9 [11.7%] vs 3 [1.7%], P = .001); 8 patients with non–clear cell RCC (10.0%) had a mutation in a gene that could guide therapy. Among all patients with mutations in RCC-associated genes, 5 (35.7%) did not meet current guidelines for genetic testing.

The investigators concluded, “Of patients with non–clear cell RCC, more than 20% had a germline mutation, of which half had the potential to direct systemic therapy. Current referral criteria for genetic testing did not identify a substantial portion of patients with mutations, supporting the role of a more inclusive sequencing approach.”

Carlo MI, et al: JAMA Oncol 4:1228-1235, 2018.


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