Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma
Abstract Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC...
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Nature Portfolio
2017
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oai:doaj.org-article:8b092046f8544ac887a7010827752cf42021-12-02T16:06:48ZRecognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma10.1038/s41598-017-07191-y2045-2322https://doaj.org/article/8b092046f8544ac887a7010827752cf42017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07191-yhttps://doaj.org/toc/2045-2322Abstract Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC gene expression profiles. Consensus clustering showed unstable subtype and principal component analysis (PCA) showed a continuous spectrum both within and between datasets. Considering the lack of discrete delineation and continuous spectrum observed, we developed a continuous quantitative prognosis score (Continuous Linear Enhanced Assessment of RCC, or CLEAR score). Prognostic performance was evaluated in independent cohorts from The Cancer Genome Atlas (TCGA) (n = 414) and EMBL-EBI (n = 53), CLEAR score demonstrated both superior prognostic estimates and inverse correlation with anti-angiogenic tyrosine-kinase inhibition in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score. 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 that average intertumoral heterogeneity exceeded intratumoral expression heterogeneity. Wider investigation of cancer biology using continuous approaches may yield insights into tumor heterogeneity; single cell analysis may provide a key foundation for this approach.Xiaona WeiYukti ChoudhuryWeng Khong LimJohn AnemaRichard J. KahnoskiBrian LaneJohn LudlowMasayuki TakahashiHiro-omi KanayamaArie BelldegrunHyung L. KimCraig RogersDavid NicolBin Tean TehMin-Han TanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017) |
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Medicine R Science Q Xiaona Wei Yukti Choudhury Weng Khong Lim John Anema Richard J. Kahnoski Brian Lane John Ludlow Masayuki Takahashi Hiro-omi Kanayama Arie Belldegrun Hyung L. Kim Craig Rogers David Nicol Bin Tean Teh Min-Han Tan Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma |
| description |
Abstract Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC gene expression profiles. Consensus clustering showed unstable subtype and principal component analysis (PCA) showed a continuous spectrum both within and between datasets. Considering the lack of discrete delineation and continuous spectrum observed, we developed a continuous quantitative prognosis score (Continuous Linear Enhanced Assessment of RCC, or CLEAR score). Prognostic performance was evaluated in independent cohorts from The Cancer Genome Atlas (TCGA) (n = 414) and EMBL-EBI (n = 53), CLEAR score demonstrated both superior prognostic estimates and inverse correlation with anti-angiogenic tyrosine-kinase inhibition in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score. 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 that average intertumoral heterogeneity exceeded intratumoral expression heterogeneity. Wider investigation of cancer biology using continuous approaches may yield insights into tumor heterogeneity; single cell analysis may provide a key foundation for this approach. |
| format |
article |
| author |
Xiaona Wei Yukti Choudhury Weng Khong Lim John Anema Richard J. Kahnoski Brian Lane John Ludlow Masayuki Takahashi Hiro-omi Kanayama Arie Belldegrun Hyung L. Kim Craig Rogers David Nicol Bin Tean Teh Min-Han Tan |
| author_facet |
Xiaona Wei Yukti Choudhury Weng Khong Lim John Anema Richard J. Kahnoski Brian Lane John Ludlow Masayuki Takahashi Hiro-omi Kanayama Arie Belldegrun Hyung L. Kim Craig Rogers David Nicol Bin Tean Teh Min-Han Tan |
| author_sort |
Xiaona Wei |
| title |
Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma |
| title_short |
Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma |
| title_full |
Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma |
| title_fullStr |
Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma |
| title_full_unstemmed |
Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma |
| title_sort |
recognizing the continuous nature of expression heterogeneity and clinical outcomes in clear cell renal cell carcinoma |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/8b092046f8544ac887a7010827752cf4 |
| work_keys_str_mv |
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