Dataset Information

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

ABSTRACT:

Purpose

Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.

Experimental design

Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.

Results

Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.

Conclusions

We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.See related commentary by McMullen et al., p. 5271.

SUBMITTER: Talhouk A

PROVIDER: S-EPMC7572656 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

Talhouk Aline A George Joshy J Wang Chen C Budden Timothy T Tan Tuan Zea TZ Chiu Derek S DS Kommoss Stefan S Leong Huei San HS Chen Stephanie S Intermaggio Maria P MP Gilks Blake B Nazeran Tayyebeh M TM Volchek Mila M Elatre Wafaa W Bentley Rex C RC Senz Janine J Lum Amy A Chow Veronica V Sudderuddin Hanwei H Mackenzie Robertson R Leong Samuel C Y SCY Liu Geyi G Johnson Dustin D Chen Billy B Group Aocs A Alsop Jennifer J Banerjee Susana N SN Behrens Sabine S Bodelon Clara C Brand Alison H AH Brinton Louise L Carney Michael E ME Chiew Yoke-Eng YE Cushing-Haugen Kara L KL Cybulski Cezary C Ennis Darren D Fereday Sian S Fortner Renée T RT García-Donas Jesús J Gentry-Maharaj Aleksandra A Glasspool Rosalind R Goranova Teodora T Greene Casey S CS Haluska Paul P Harris Holly R HR Hendley Joy J Hernandez Brenda Y BY Herpel Esther E Jimenez-Linan Mercedes M Karpinskyj Chloe C Kaufmann Scott H SH Keeney Gary L GL Kennedy Catherine J CJ Köbel Martin M Koziak Jennifer M JM Larson Melissa C MC Lester Jenny J Lewsley Liz-Anne LA Lissowska Jolanta J Lubiński Jan J Luk Hugh H Macintyre Geoff G Mahner Sven S McNeish Iain A IA Menkiszak Janusz J Nevins Nikilyn N Osorio Ana A Oszurek Oleg O Palacios José J Hinsley Samantha S Pearce Celeste L CL Pike Malcolm C MC Piskorz Anna M AM Ray-Coquard Isabelle I Rhenius Valerie V Rodriguez-Antona Cristina C Sharma Raghwa R Sherman Mark E ME De Silva Dilrini D Singh Naveena N Sinn Peter P Slamon Dennis D Song Honglin H Steed Helen H Stronach Euan A EA Thompson Pamela J PJ Tołoczko Aleksandra A Trabert Britton B Traficante Nadia N Tseng Chiu-Chen CC Widschwendter Martin M Wilkens Lynne R LR Winham Stacey J SJ Winterhoff Boris B Beeghly-Fadiel Alicia A Benitez Javier J Berchuck Andrew A Brenton James D JD Brown Robert R Chang-Claude Jenny J Chenevix-Trench Georgia G deFazio Anna A Fasching Peter A PA García María J MJ Gayther Simon A SA Goodman Marc T MT Gronwald Jacek J Henderson Michelle J MJ Karlan Beth Y BY Kelemen Linda E LE Menon Usha U Orsulic Sandra S Pharoah Paul D P PDP Wentzensen Nicolas N Wu Anna H AH Schildkraut Joellen M JM Rossing Mary Anne MA Konecny Gottfried E GE Huntsman David G DG Huang Ruby Yun-Ju RY Goode Ellen L EL Ramus Susan J SJ Doherty Jennifer A JA Bowtell David D DD Anglesio Michael S MS

Clinical cancer research : an official journal of the American Association for Cancer Research 20200617 20

<h4>Purpose</h4>Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previousl ...[more]

PMID: 32554541

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Project description:Multiple studies have identified transcriptome subtypes of high-grade serous ovarian carcinoma (HGSOC), but their interpretation and translation are complicated by tumor evolution and polyclonality accompanied by extensive accumulation of somatic aberrations, varying cell type admixtures, and different tissues of origin. In this study, we examined the chronology of HGSOC subtype evolution in the context of these factors using a novel integrative analysis of absolute copy-number analysis and gene expression in The Cancer Genome Atlas complemented by single-cell analysis of six independent tumors. Tumor purity, ploidy, and subclonality were reliably inferred from different genomic platforms, and these characteristics displayed marked differences between subtypes. Genomic lesions associated with HGSOC subtypes tended to be subclonal, implying subtype divergence at later stages of tumor evolution. Subclonality of recurrent HGSOC alterations was evident for proliferative tumors, characterized by extreme genomic instability, absence of immune infiltration, and greater patient age. In contrast, differentiated tumors were characterized by largely intact genome integrity, high immune infiltration, and younger patient age. Single-cell sequencing of 42,000 tumor cells revealed widespread heterogeneity in tumor cell type composition that drove bulk subtypes but demonstrated a lack of intrinsic subtypes among tumor epithelial cells. Our findings prompt the dismissal of discrete transcriptome subtypes for HGSOC and replacement by a more realistic model of continuous tumor development that includes mixtures of subclones, accumulation of somatic aberrations, infiltration of immune and stromal cells in proportions correlated with tumor stage and tissue of origin, and evolution between properties previously associated with discrete subtypes. SIGNIFICANCE: This study infers whether transcriptome-based groupings of tumors differentiate early in carcinogenesis and are, therefore, appropriate targets for therapy and demonstrates that this is not the case for HGSOC.

Project description:BackgroundEnhancer of zesta homologue 2 (EZH2) is an essential component of polycomb repressive complex 2 (PRC2) that contributes to tumor progression and chemo-resistance. The aim of this study was to comprehensively assess the prognostic value of EZH2 across the morphologic and molecular spectra of high-grade serous ovarian carcinoma (HGSOC) by utilizing both immunohistochemistry (IHC) and proteogenomic technologies.MethodsIHC of EZH2 was performed using a tissue microarray of 79 HGSOC scored (+/-) for lymphovascular invasion (LVI), tumor-infiltrating lymphocytic aggregates ≥1 mm (TIL) and architectural growth patterns. The association of EZH2 H-score with response to therapy and overall survival was evaluated by tumor features. We also evaluated EZH2 transcriptional (RNA sequencing) and protein (mass spectrometry) expression from bulk tumor samples from 336 HGSOC from The Cancer Genome Atlas (TCGA). EZH2 expression and co-expression networks were compared by clinical outcomes.ResultsFor HGSOC without TIL (58%), EZH2 expression was almost 2-fold higher in platinum resistant tumors (P = 0.01). Conversely, EZH2 was not associated with platinum resistance among TIL+ HGSOC (P = 0.41). EZH2 expression was associated with reduced survival for tumors with LVI (P = 0.04). Analysis of TCGA found higher EZH2 expression in immunoreactive and proliferative tumors (P = 6.7 × 10- 5) although protein levels were similar across molecular subtypes (P = 0.52). Both mRNA and protein levels of EZH2 were lower in platinum resistant tumors although they were not associated with survival. Co-expression analysis revealed EZH2 networks totaling 1049 mRNA and 448 proteins that were exclusive to platinum sensitive or resistant tumors. The EZH2 network in resistant HGSOC included CARM1 which was positively correlated with EZH2 at both mRNA (r = 0.33, p = 0.003) and protein (r = 0.14, P = 0.01) levels. Further, EZH2 co-expression with CARM1 corresponded to a decreased prognostic significance of EZH2 expression in resistant tumors.ConclusionsOur findings demonstrate that EZH2 expression varies based on its interactions with immunologic pathways and tumor microenvironment, impacting the prognostic interpretation. The association between high EZH2 expression and platinum resistance in TIL- HGSOC warrants further study of the implications for therapeutic strategies.

Dataset Information

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

Purpose

Experimental design

Results

Conclusions

Publications

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

Similar Datasets

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