Urologic Oncology: Seminars and Original Investigations
Original articleGenomic alterations as predictors of survival among patients within a combined cohort with clear cell renal cell carcinoma undergoing cytoreductive nephrectomy☆
Introduction
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive histologic subtype of renal cell carcinoma [1]. Metastatic disease is present in ~33% of patients at time of presentation, with a 5-year survival rate of ~12% for patients with distant metastases [2].
The foundational genomic aberrations in ccRCC are understood to take place in concert with chromosome 3p loss [3], [4]. Although VHL alterations are common in ccRCC, it has been shown that VHL alterations alone are inadequate for the development of ccRCC: other alterations are required for tumorigenesis [5]. Recurrently mutated genes have been found in several large ccRCC cohorts with the following frequencies: VHL—75–80%, polybromo-1 (PBRM1)—35–45%, set domain containing 2 (SETD2)—5–15%, and BRCA1 associated protein-1 (BAP1)—5–15% [4], [6]. We and others have reported associations between these genomic alterations and inferior clinical outcomes, mainly in the localized disease setting [7], [8], [9], [10], [11], [12], [13]. Several studies have attempted to use the mutation status of these genes to stratify patients and predict their risk of poor clinical outcomes [14], [15], [16].
One such stratification scheme has been based on the mutation status of PBRM1 and BAP1 in patients with ccRCC. Joseph et al. reported the significance of these genes in a large cohort of patients with mostly localized ccRCC using immunohistochemistry. They found that patients with neither mutation had the best clinical outcomes, whereas patients with mutations in PBRM1, BAP1, or both, had sequentially worse outcomes [10]. Numerous other studies have identified inferior overall survival (OS) in patients carrying BAP1 mutations [6], [14].
To our knowledge the relevance of these mutations in patients undergoing cytoreductive nephrectomy (CN) remains unknown. In our study, we analyze the effects of recurrent somatic mutations, in particular BAP1 and PBRM1, in patients׳ primary tumors and the mutations׳ associations with survival in the setting of patients with ccRCC undergoing CN.
Section snippets
Patient selection
Upon approval by the institutional review board at Memorial Sloan Kettering Cancer Center (MSKCC), we queried our prospectively collected institutional kidney cancer genomic database for patients with AJCC stage IV ccRCC between January 1, 2001 and December 31, 2015 (461 patients). This database includes pathological data including histology, grade, and stage, as well as clinical data including survival data. Of those queried patients, 70 patients had their primary tumors sequenced at time of
Demographics
Demographic and clinicopathological characteristics of our cohort of 167 patients are described in Table 1, along with univariable associations with OS. Median age was 60 years (range: 39–84) and the most were male (69.5%). Median follow-up time was 3 years (range: 0.3–10.6); during follow-up, 105 patients died of any cause. Median OS was 2.5 years (95% CI: 2.0–3.4). On univariable analysis, the only characteristic found to be significantly associated with decreased OS was worsening Fuhrman
Discussion
To our knowledge this is the first analysis of the role of genomic alterations on clinical outcomes among a cohort of cytoreductive patients with ccRCC. In this study we evaluated associations between select recurrent somatic mutations and OS for cytoreductive patients. We found BAP1 mutations were associated with inferior OS, whereas SETD2 and KDM5C were associated with improved OS.
Using a BAP1/PBRM1 stratification scheme for prognosis, we found no statistically significant difference in OS
Conclusion
In our study of 167 cytoreductive patients with ccRCC, we found that mutations in BAP1 negatively affected OS, whereas SETD2 and KDM5C mutations were associated with prolonged OS. Our results expand upon previously described efforts at understanding genomic biomarkers in localized disease. Those efforts set the stage for our novel investigation examining the specific association of selected recurrent somatic mutations in stage IV patients with ccRCC ideally in the clinical trial setting. The
References (27)
Clear cell renal cell carcinoma subtypes identified by BAP1 and PBRM1 expression
J Urol
(2016)Wild-type VHL clear cell renal cell carcinomas are a distinct clinical and histologic entity: a 10-year follow-up
Eur Urol Focus
(2016)Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma
Eur Urol
(2013)Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology
J Mol Diagn
(2015)Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation
Lancet Oncol
(2013)Correlation between molecular subclassifications of clear cell renal cell carcinoma and targeted therapy response
Eur Urol Focus
(2016)The Global Burden of Cancer 2013
JAMA Oncol
(2015)- SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Available from: http://seer.cancer.gov/statfacts/html/kidrp.html...
- et al.
A clear picture of renal cell carcinoma
Nat Genet
(2013) Comprehensive molecular characterization of clear cell renal cell carcinoma
Nature
(2013)
VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400
Nat Cell Biol
Integrated molecular analysis of clear-cell renal cell carcinoma
Nat Genet
VHL gene mutations in renal cell carcinoma: role as a biomarker of disease outcome and drug efficacy
Curr Oncol Rep
Cited by (20)
Current Landscape of Genomic Biomarkers in Clear Cell Renal Cell Carcinoma
2023, European UrologyHarnessing the Genomic Landscape of the Small Renal Mass to Guide Clinical Management
2019, European Urology FocusCitation Excerpt :In all, 203 patients were included in the analysis, with 23 (11.3%) patients having either recurrence or death from disease, and mutations in KDM5C were found to be significantly associated with poor outcomes. Additionally, the absence of mutations known to be associated with metastatic disease and poor clinical outcomes including BAP1, SETD2, and TP53 can also aid in the management of SRMs [51–54]. While these studies (Table 1) have brought to light several statistically significant genomic alterations in RCC, their results have primarily been aimed at patients with advanced/metastatic ccRCC and derived from surgical tumor specimens.
Individualised Indications for Cytoreductive Nephrectomy: Which Criteria Define the Optimal Candidates?
2019, European Urology OncologyCitation Excerpt :Others have advocated the use of Eastern Cooperative Oncology Group performance status [51] or sarcopenia [65] as potential prognostic factors. Only one study reported on the potential prognostic effect of recurrent somatic mutations in a predefined set of genes [66]; however, clinical implementation of these data is not possible since no indication for decision making is presented. Moreover, this study was based on biopsy-derived tissue but not on CN specimen-derived sample, therefore limiting the clinical applicability.
Prognostic and clinicopathological value of PBRM1 expression in renal cell carcinoma
2018, Clinica Chimica ActaCitation Excerpt :Kapur P et al. [26] first evaluated the effects on survival of PBRM1 mutations in sporadic ccRCC. In addition, there were also two studies evaluated the relations between PBRM1 mutations and outcomes [24,25], the results were inconsistent. In this study, to reduce the heterogeneity induced by different detection methods, we only focused on validating PBRM1 immunohistochemical expression and evaluated the prognostic values of decreased expression of PBRM1 in RCC.
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Supported by the Sidney Kimmel Center for Prostate and Urologic Cancers and the NIH/NCI Cancer Center Support grant P30 CA008748 and Ruth L. Kirschstein National Research Service Award T32CA082088.