RT Journal Article
SR Electronic
T1 Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 044891
DO 10.1101/044891
A1 Xiaona Wei
A1 Yukti Choudhury
A1 Weng Khong Lim
A1 John Anema
A1 Richard J. Kahnoski
A1 Brian Lane
A1 John Ludlow
A1 Masayuki Takahashi
A1 Hiro-omi Kanayama
A1 Arie Belldegrun
A1 Hyung L. Kim
A1 Craig Rogers
A1 David Nicol
A1 Bin Tean Teh
A1 Min-Han Tan
YR 2016
UL http://biorxiv.org/content/early/2016/03/25/044891.abstract
AB PURPOSE Evaluation of 12 ccRCC publicly-available ccRCC gene expression datasets showed that previously proposed discrete molecular subtypes are unstable. To reflect the continuous nature of gene expression observed, we developed a quantitative score (Continuous Linear Enhanced Assessment of Renal cell carcinoma, or CLEAR) using expression analysis founded on pathologic parameters.MATERIALS AND METHODS 265 ccRCC gene expression profiles were used to develop the CLEAR score, representing a genetic correlate of the continuum of morphological tumor grade. A signature derivation method based on correlation of CLEAR score with gene expression ranking was used to derive an 18-transcript signature. External validation was conducted in multiple public expression datasets.Results As a measure of intertumoral gene expression heterogeneity, the CLEAR score demonstrated both superior prognostic estimates (94% vs 83% adequacy index in TCGA dataset) and inverse correlation with anti-angiogenic tyrosine-kinase inhibition (65% vs 55% adequacy index) in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score (p=0.05). Multiple somatic mutations (VHL, PBRM1, SETD2, KDM5C, TP53, BAP1, PTEN, MTOR) were associated with the CLEAR score. Application of the CLEAR score to independent expression profiling of intratumoral ccRCC regions demonstrated its ability to reflect intratumoral expression heterogeneity and further analysis showed average intertumoral heterogeneity exceeded intratumoral heterogeneity.Conclusions The CLEAR score, a gene expression signature developed on histopathology, outperformed discrete subtype-classification in prognostic estimates and correlated better with treatment outcomes. Recognizing cancer as a continuum has important implications for laboratory and clinical research.