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Differential prognostic value of MYC immunohistochemistry in subtypes of papillary renal cell carcinoma.

ABSTRACT: The histomorphological subtyping of papillary renal cell carcinomas (pRCCs) has improved the predictions of patients' long-term survival. Based on our previous results, we hypothesized that the MYC proto-oncogene would show differential expression in pRCC subtypes. Using a multi-institutional cohort of 204 pRCC patients we assessed the additional value of the immunohistochemical markers MYC, MINA53, and Ki67 in predicting patient's long-term survival. The clinical endpoints were overall survival (OS) and cancer-specific survival (CSS). Nomograms were constructed to predict each patient's risk of death (OS). The incorporation of the MYC staining patterns allowed the stratification of pRCC type 1 patients into better and worse prognostic groups. None of the patients with pRCC type 1 tumors and favorable MYC staining patterns died from tumor-related causes. This prognostic value was independent of the patient's age at surgery, the pathological tumor stage and presence of lymph node invasion. we could show that the immunohistochemical assessment of MYC and the histomorphological subtyping of pRCC stratifies pRCC type 1 tumors with regard to OS and CSS. The determination of the histomorphologic pRCC subtype in combination with the MYC immunohistochemical staining patterns allows a more accurate prediction of patients' individual risk of death.

SUBMITTER: Bellut J

PROVIDER: S-EPMC5703709 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Differential prognostic value of MYC immunohistochemistry in subtypes of papillary renal cell carcinoma.

Bellut Julia J Bertz Simone S Nolte Elke E Stöhr Christine C Polifka Iris I Lieb Verena V Herrmann Edwin E Jung Rudolf R Hartmann Arndt A Wullich Bernd B Taubert Helge H Wach Sven S

Scientific reports 20171127 1

The histomorphological subtyping of papillary renal cell carcinomas (pRCCs) has improved the predictions of patients' long-term survival. Based on our previous results, we hypothesized that the MYC proto-oncogene would show differential expression in pRCC subtypes. Using a multi-institutional cohort of 204 pRCC patients we assessed the additional value of the immunohistochemical markers MYC, MINA53, and Ki67 in predicting patient's long-term survival. The clinical endpoints were overall survival ...[more]

PMID: 29180625

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Project description:IntroductionGene-expression signatures for prognosis have been reported in localized renal cell carcinoma (RCC). The aim of this study was to test the predictive power of two different signatures, ClearCode34, a 34-gene signature model [Eur Urol 2014;66:77-84], and an 8-gene signature model [Eur Urol 2015;67:17-20], in the setting of systemic therapy for metastatic disease.Materials and methodsMetastatic RCC (mRCC) patients from five institutions who were part of TCGA were identified and clinical data were retrieved. We trained and implemented each gene model as described by the original study. The latter was demonstrated by faithful regeneration of a figure and results from the original study. mRCC patients were dichotomized to good or poor prognostic risk groups using each gene model. Cox proportional hazard regression and concordance index (C-Index) analysis were used to investigate an association between each prognostic risk model and overall survival (OS) from first-line therapy.ResultsOverall, 54 patients were included in the final analysis. The primary endpoint was OS. Applying the ClearCode34 model, median survival for the low-risk-ccA (n = 17)-and the high-risk-ccB (n = 37)-subtypes were 27.6 and 22.3 months (hazard ratio (HR): 2.33; p = .039), respectively. ClearCode34 ccA/ccB and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classifications appear to represent distinct risk criteria in mRCC, and we observed no significant overlap in classification (p > .05, chi-square test). On multivariable analyses and adjusting for IMDC groups, ccB remained independently associated with a worse OS (p = .044); the joint model of ccA/ccB and IMDC was significantly more accurate in predicting OS than a model with IMDC alone (p = .045, F-test). This was also observed in C-Index analysis; a model with both ccA and ccB subtypes had higher accuracy (C-Index 0.63, 95% confidence interval [CI] = 0.51-0.75) and 95% CIs of the C-Index that did not include the null value of 0.5 in contrast to a model with IMDC alone (0.60, CI = 0.47-0.72). The 8-gene signature molecular subtype model was a weak but insignificant predictor of survival in this cohort (p = .13). A model that included both the 8-gene signature and IMDC (C-Index 0.62, CI = 0.49-0.76) was more prognostic than IMDC alone but did not reach significance, as the 95% CI included the null value of 0.5. These two genomic signatures share no genes in common and are enriched in different biological pathways. The ClearCode34 included genes ARNT and EPAS1 (also known as HIF2a), which are involved in regulation of gene expression by hypoxia-inducible factor.ConclusionThe ClearCode34 but not the 8-gene molecular model improved the prognostic predictive power of the IMDC model in this cohort of 54 patients with metastatic clear cell RCC. The Oncologist 2017;22:286-292 IMPLICATIONS FOR PRACTICE: The clinical and laboratory factors included in the International Metastatic Renal Cell Carcinoma Database Consortium model provide prognostic information in metastatic renal cell carcinoma (mRCC). The present study shows that genomic signatures, originally validated in localized RCC, may add further complementary prognostic information in the metastatic setting. This study may provide new insights into the molecular basis of certain mRCC subgroups. The integration of clinical and molecular data has the potential to redefine mRCC classification, enhance the understanding of mRCC biology, and potentially predict response to treatment in the future.

Project description:The aim of the present study was to identify long non-coding RNA (lncRNA)-based prognostic biomarkers in papillary renal cell carcinoma (pRCC). lncRNA expression data and corresponding clinical data from patients with pRCC were obtained from The Cancer Genome Atlas. R software and packages were used for data analysis. Univariate Cox regression analysis and least absolute shrinkage and selection operator regression were performed to identify key lncRNAs, which were then used to construct a prognostic model using multivariate Cox regression analysis. Patients were divided into high- and low-risk groups, and Kaplan-Meier (KM) survival curves and time-dependent receiver operating characteristic (ROC) curves were plotted. The C-index was calculated to estimate the model's prognostic power. The hazard ratio (HR), 95% confidence interval (CI), and statistical significance of each key lncRNA were also calculated by multivariate Cox regression. Based on the result of the multivariate Cox regression analysis, KM survival plots were plotted for each significantly associated lncRNA. The subcellular locations of the prognostic biomarkers were predicted using lncRNAMap and lncLocator. A total of 17 lncRNA signatures were identified as key lncRNAs. Overall survival rate was significantly higher in the low-risk group compared with the high-risk group. The areas under the ROC curve were 0.93 (3-year ROC) and 0.902 (5-year ROC), and the C-index was 0.915. A forest plot was used to illustrate the HR and 95% CI of key lncRNAs. KM survival analysis revealed the prognostic significance of two protective biomarkers, AC024022.1 and GAS6-AS1, and three adverse biomarkers, AC087379.2, AL352984.1, and AL499627.1. It was predicted that AC024022.1 and AC087379.2 may be located in the cytoplasm and GAS6-AS1 may be located in the cytosol. The present study may contribute to the management of pRCC and serve as a foundation for further investigations into the underlying mechanism of tumorigenesis and progression of pRCC.

Dataset Information

Differential prognostic value of MYC immunohistochemistry in subtypes of papillary renal cell carcinoma.

Publications

Differential prognostic value of MYC immunohistochemistry in subtypes of papillary renal cell carcinoma.

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