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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.

SUBMITTER: Manley BJ

PROVIDER: S-EPMC5984192 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Manley Brandon J BJ Reznik Ed E Ghanaat Mazyar M Kashan Mahyar M Becerra Maria F MF Casuscelli Jozefina J Tennenbaum Daniel D Redzematovic Almedina A Carlo Maria I MI Sato Yusuke Y Arcila Maria M Voss Martin H MH Feldman Darren R DR Motzer Robert J RJ Russo Paul P Coleman Jonathan J Hsieh James J JJ Hakimi Ari A AA

Urologic oncology 20171111 1

<h4>Introduction</h4>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.<h4>Methods</h4>We identified patients who had SRMs (4cm or less) at time of surgery, had sequencing p ...[more]

PMID: 29132830

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Project description:BACKGROUND:Analyses of associations between clinicopathologic outcomes and recurrent somatic mutations in clear cell renal cell carcinoma (ccRCC) have been limited to individual cohorts. OBJECTIVE:To define clinicopathologic associations between specific mutations and ccRCC disease characteristics. DESIGN, SETTING, AND PARTICIPANTS:DNA sequencing data were pooled from three collaborative genomic cohorts (n=754) and our institutional database (n=295). All patients had clinical data and identification of somatic mutations from their primary tumors. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Analysis of gene mutations for associations with maximal tumor size (linear regression) and pathologic stage (logistic regression). Cancer-specific survival (CSS) and recurrence-free survival (RFS) were calculated using competing risks methods. Analyses were adjusted for cohort site, and results were adjusted for multiple testing (q value). Relevant genes were used in multivariable models that included confounding variables and the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. RESULTS AND LIMITATIONS:Association with tumor size was found for mutations in BAP1 (q=0.013). No mutations were found to be associated with stage after adjusted analysis. Mutations in BAP1 (q=0.004) and TP53 (q=0.001) were associated with decreased CSS in a multivariable model; only TP53 (q=0.005) remained significant when SSIGN score was included. SETD2 mutations (q=0.047) were associated with decreased RFS in multivariable models, including models with SSIGN score. CONCLUSIONS:In >1000 patients with ccRCC, pooled analysis and multivariable modeling demonstrated that three mutated genes have statistically significant associations with poor clinical outcomes. This included the more commonly mutated BAP1 and SETD2 and the less frequently mutated TP53. After adjustment for clinical confounders, mutations of TP53 and SETD2 were associated with decreased CSS and RFS, respectively. PATIENT SUMMARY:Using rigorous statistical methods, this study affirmed that certain mutations in clear cell renal cell carcinoma may portend inferior survival and an increased risk of recurrence.

Project description:BACKGROUND. The lack of validated imaging markers to characterize biologic aggressiveness of small renal masses (SRMs)-defined as those categorized as cT1a and 4 cm and smaller-hinders medical decision-making among available initial management strategies. OBJECTIVE. The purpose of this article was to explore the association of the clear cell likelihood score (ccLS) on MRI with growth rates and progression of SRMs. METHODS. This retrospective study included consecutive SRMs assigned a ccLS on clinical MRI examinations performed between June 2016 and November 2019 at an academic tertiary-care medical center or its affiliated safety net hospital system. The ccLS reports the likelihood that the SRM represents clear cell renal cell carcinoma (ccRCC) from 1 (very unlikely) to 5 (very likely). The ccLS was extracted from clinical reports. Tumor size measurements were extracted from available prior and follow-up cross-sectional imaging examinations, through June 2020. Serial tumor size measurements were fit to linear and exponential growth curves. Estimated growth rates were grouped by the assigned ccLS. Tumor progression was defined by development of large size (> 4 cm in at least two consecutive measurements) and/or rapid growth (doubling of volume within 1 year). Differences among ccLS groups were evaluated using Kruskal-Wallis tests. Correlations between ccLS and growth rate were evaluated by Spearman correlation (ρ). RESULTS. Growth rates of 386 SRMs (100 ccLS 1-2, 75 ccLS 3, and 211 ccLS 4-5) from 339 patients (median age, 65 years; 198 men, 141 women) were analyzed. Median follow-up was 1.2 years. The ccLS was correlated with growth rates by size (ρ = 0.19; p < .001; ccLS 4-5, 9%/year; ccLS 1-2, 5%/year; p < .001) and by volume (ρ = 0.14; p = .006; ccLS 4-5, 29%/year; ccLS 1-2, 16%/year; p < .001). Disease progression (observed in 49 SRMs) was not significantly associated with ccLS group (p = .61). Two patients (0.6%) developed metastases during active surveillance: one ccLS 1 was a type 2 papillary renal cell carcinoma and one ccLS 4 was ccRCC. CONCLUSION. Growth is associated with ccLS in SRMs, with higher ccLS correlating with faster growth. CLINICAL IMPACT. SRMs with lower ccLS may be considered for active surveillance, whereas SRMs with higher ccLS may warrant earlier intervention. The noninvasive ccLS derived from MRI correlates with growth rate of SRMs and may help guide personalized management.

Project description:The majority of renal cell carcinoma (RCC) is now incidentally detected and presents as small renal masses (SRMs) defined as ≤ 4 cm in size. SRMs are heterogeneous comprising several histological types of RCC each with different biology and behavior, and benign tumors mainly oncocytoma. The varied prognosis of the different types of renal tumor has implications for management options. A key epigenetic alteration involved in the initiation and progression of cancer is aberrant methylation in the promoter region of a gene. The hypermethylation is associated with transcriptional repression and is an important mechanism of inactivation of tumor suppressor genes in neoplastic cells. We have determined the genome-wide promoter methylation profiles of 47 pT1a and 2 pT1b clear cell, papillary or chromophobe RCC, 25 benign renal oncocytoma ≤ 4 cm and 4 normal renal parenchyma specimens by Infinium HumanMethylation27 beadchip technology. We identify gene promoter hypermethylation signatures that distinguish clear cell and papillary from each other, from chromophobe and oncocytoma, and from normal renal cells. Pairwise comparisons revealed genes aberrantly hypermethylated in a tumor type but unmethylated in normal, and often unmethylated in the other renal tumor types. About 0.4% to 1.7% of genes comprised the promoter methylome in SRMs. The Infinium methylation score for representative genes was verified by gold standard technologies. The genes identified as differentially methylated implicate pathways involved in metabolism, tissue response to injury, epithelial to mesenchymal transition (EMT), signal transduction and G-protein coupled receptors (GPCRs), cancer, and stem cell regulation in the biology of RCC. Our findings contribute towards an improved understanding of the development of RCC, the different biology and behavior of histological types, and discovery of molecular subtypes. The differential methylation signatures may have utility in early detection and particularly differential diagnosis for prognostic stratification as well as identify novel gene and pathway targets for therapeutic intervention.

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

Publications

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

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