Characterizing recurrent and lethal small renal masses in clear cell renal cell carcinoma using recurrent somatic mutations

Abstract

Introduction: Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance.

Methods: We identified patients who had SRMs (4cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC. Patients were selected from 3 publicly available cohorts, The Cancer Genome Atlas (n = 110), University of Tokyo (n = 37), The International Cancer Genome Consortium (n = 31), and from our own institutional prospective database (n = 25). Among this cohort we analyzed mutations present in at least 5% of tumors, assessing for the enrichment of mutations and progression-free survival using the composite endpoint of recurrence or death of disease. Analysis was adjusted for multiple testing. A Cox regression model was used to assess clinical variables with significant mutations.

Results: In total, 203 patients were available for analysis. Median follow-up was 43.1 months among survivors. Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C, and MTOR were present in more than 5% of tumors. Twenty-three patients (11.3%) had recurrence or died of their disease. Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P 0.033.

Conclusions: We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality. The strongest association was seen in those with KDM5C mutations. Use of these genomic biomarkers may improve stratification of patients with SRMs and for those who may be appropriate for active surveillance. Prospective evaluation of these markers is needed.

Keywords: Genomic biomarkers; KDM5C; Risk stratification; Small renal masses; mutations.

Fig. 1

Depiction of the frequency and co-occurrence of mutations in a cohort of patients who had recurrence or died of their disease (A), and patients who were alive without recurrence (B)

Fig. 1

Depiction of the frequency and co-occurrence of mutations in a cohort of patients who had recurrence or died of their disease (A), and patients who were alive without recurrence (B)

Fig. 2

Kaplan-Meier survival plot comparing risk of recurrence or death of disease between patients with wild type and KDM5C mutations in their primary tumor