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Eur Urol. 2014 Nov;66(5):936-48. doi: 10.1016/j.eururo.2014.06.053. Epub 2014 Jul 19.

Systematic evaluation of the prognostic impact and intratumour heterogeneity of clear cell renal cell carcinoma biomarkers.

Author information

1
Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, UK.
2
Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK.
3
Centre for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
4
The Royal Marsden Hospital, London, UK.
5
Centre for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark; Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, USA.
6
Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, UK. Electronic address: paul.batest@cancer.org.uk.
7
Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK; UCL Cancer Institute, London, UK. Electronic address: charles.swanton@cancer.org.uk.
8
Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK; Present address: Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.

Abstract

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.

KEYWORDS:

Biomarker; Intratumour heterogeneity; Kidney cancer; Personalised medicine; Prognostic marker

PMID:
25047176
PMCID:
PMC4410302
DOI:
10.1016/j.eururo.2014.06.053
[Indexed for MEDLINE]
Free PMC Article

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