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Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)
- Source :
- Clinical Cancer Research. 26:5411-5423
- Publication Year :
- 2020
- Publisher :
- American Association for Cancer Research (AACR), 2020.
-
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
- Subjects :
- 0301 basic medicine
Oncology
Cancer Research
medicine.medical_specialty
Neoplasm, Residual
Bevacizumab
03 medical and health sciences
Ovarian tumor
Lymphocytes, Tumor-Infiltrating
0302 clinical medicine
Ovarian carcinoma
Internal medicine
medicine
Humans
1112 Oncology and Carcinogenesis
Oncology & Carcinogenesis
Stage (cooking)
Aged
Ovarian Neoplasms
business.industry
Cystadenoma, Serous
Cancer
Middle Aged
Precision medicine
Omics
medicine.disease
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
Serous fluid
030104 developmental biology
030220 oncology & carcinogenesis
Female
Neoplasm Grading
Transcriptome
business
Algorithms
medicine.drug
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 26
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....bde75a52c672f987ad27c063d5669c57