Systematic evaluation of the prognostic impact and intratumour heterogeneity of clear cell renal cell carcinoma biomarkers.
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Date
2014-07-19ICR Author
Author
Gulati, S
Martinez, P
Joshi, T
Birkbak, NJ
Santos, CR
Rowan, AJ
Pickering, L
Gore, M
Larkin, J
Szallasi, Z
Bates, PA
Swanton, C
Gerlinger, M
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: Candidate biomarkers have been identified for clear cell renal cell carcinoma (ccRCC) patients, but most have not been validated. OBJECTIVE: To validate published ccRCC prognostic biomarkers in an independent patient cohort and to assess intratumour heterogeneity (ITH) of the most promising markers to guide biomarker optimisation. DESIGN, SETTING, AND PARTICIPANTS: Cancer-specific survival (CSS) for each of 28 identified genetic or transcriptomic biomarkers was assessed in 350 ccRCC patients. ITH was interrogated in a multiregion biopsy data set of 10 ccRCCs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biomarker association with CSS was analysed by univariate and multivariate analyses. RESULTS AND LIMITATIONS: A total of 17 of 28 biomarkers (TP53 mutations; amplifications of chromosomes 8q, 12, 20q11.21q13.32, and 20 and deletions of 4p, 9p, 9p21.3p24.1, and 22q; low EDNRB and TSPAN7 expression and six gene expression signatures) were validated as predictors of poor CSS in univariate analysis. Tumour stage and the ccB expression signature were the only independent predictors in multivariate analysis. ITH of the ccB signature was identified in 8 of 10 tumours. Several genetic alterations that were significant in univariate analysis were enriched, and chromosomal instability indices were increased in samples expressing the ccB signature. The study may be underpowered to validate low-prevalence biomarkers. CONCLUSIONS: The ccB signature was the only independent prognostic biomarker. Enrichment of multiple poor prognosis genetic alterations in ccB samples indicated that several events may be required to establish this aggressive phenotype, catalysed in some tumours by chromosomal instability. Multiregion assessment may improve the precision of this biomarker. PATIENT SUMMARY: We evaluated the ability of published biomarkers to predict the survival of patients with clear cell kidney cancer in an independent patient cohort. Only one molecular test adds prognostic information to routine clinical assessments. This marker showed good and poor prognosis results within most individual cancers. Future biomarkers need to consider variation within tumours to improve accuracy.
Collections
Subject
Humans
Carcinoma, Renal Cell
Kidney Neoplasms
Genetic Predisposition to Disease
Biopsy
Neoplasm Staging
Multivariate Analysis
Proportional Hazards Models
Risk Factors
Reproducibility of Results
Predictive Value of Tests
Gene Expression Profiling
DNA Mutational Analysis
Gene Expression Regulation, Neoplastic
Phenotype
Mutation
Polymorphism, Single Nucleotide
Time Factors
Aged
Middle Aged
Female
Male
Kaplan-Meier Estimate
Transcriptome
Biomarkers, Tumor
Research team
Melanoma and Kidney Cancer
Translational Oncogenomics
Language
eng
Date accepted
2014-06-30
License start date
2014-11
Citation
European urology, 2014, 66 (5), pp. 936 - 948
Publisher
ELSEVIER