Dataset Information

The Impact of Stroma Admixture on Molecular Subtypes and Prognostic Gene Signatures in Serous Ovarian Cancer.

ABSTRACT:

Background

Recent efforts to improve outcomes for high-grade serous ovarian cancer, a leading cause of cancer death in women, have focused on identifying molecular subtypes and prognostic gene signatures, but existing subtypes have poor cross-study robustness. We tested the contribution of cell admixture in published ovarian cancer molecular subtypes and prognostic gene signatures.

Methods

Gene signatures of tumor and stroma were developed using paired microdissected tissue from two independent studies. Stromal genes were investigated in two molecular subtype classifications and 61 published gene signatures. Prognostic performance of gene signatures of stromal admixture was evaluated in 2,527 ovarian tumors (16 studies). Computational simulations of increasing stromal cell proportion were performed by mixing gene-expression profiles of paired microdissected ovarian tumor and stroma.

Results

Recently described ovarian cancer molecular subtypes are strongly associated with the cell admixture. Tumors were classified as different molecular subtypes in simulations where the percentage of stromal cells increased. Stromal gene expression in bulk tumors was associated with overall survival (hazard ratio, 1.17; 95% confidence interval, 1.11-1.23), and in one data set, increased stroma was associated with anatomic sampling location. Five published prognostic gene signatures were no longer prognostic in a multivariate model that adjusted for stromal content.

Conclusions

Cell admixture affects the interpretation and reproduction of ovarian cancer molecular subtypes and gene signatures derived from bulk tissue. Elucidating the role of stroma in the tumor microenvironment and in prognosis is important.

Impact

Single-cell analyses may be required to refine the molecular subtypes of high-grade serous ovarian cancer.

SUBMITTER: Schwede M

PROVIDER: S-EPMC7448721 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

The Impact of Stroma Admixture on Molecular Subtypes and Prognostic Gene Signatures in Serous Ovarian Cancer.

Schwede Matthew M Waldron Levi L Mok Samuel C SC Wei Wei W Basunia Azfar A Merritt Melissa A MA Mitsiades Constantine S CS Parmigiani Giovanni G Harrington David P DP Quackenbush John J Birrer Michael J MJ Culhane Aedín C AC

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20191223 2

<h4>Background</h4>Recent efforts to improve outcomes for high-grade serous ovarian cancer, a leading cause of cancer death in women, have focused on identifying molecular subtypes and prognostic gene signatures, but existing subtypes have poor cross-study robustness. We tested the contribution of cell admixture in published ovarian cancer molecular subtypes and prognostic gene signatures.<h4>Methods</h4>Gene signatures of tumor and stroma were developed using paired microdissected tissue from t ...[more]

PMID: 31871106

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Project description:Epithelial ovarian cancer is morphologically and clinically heterogeneous. Transcriptional profiling has revealed molecular subtypes (referred to as “C-signatures”) that correlate to biological as well as clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and to investigate similarities to the intrinsic molecular subtypes of breast cancer. Global gene expression profiling was performed using Illumina's HT12 Bead Arrays and applied to 59 fresh-frozen ovarian tumors. SAM analysis revealed enrichment of cell cycel processes among the malignant tumors, in line with malignant tumors being highly proliferative. The borderline tumors were split between the malignant and benign tumor clusters, indicating that borderline tumors have both malignant and benign features. Furthermore, nearest centroid classification was performed applying previously published gene profiles for the ovarian cancer C-signatures and the intrinsic breast cancer subtypes, respectively, and showed significant correlations between the malignant serous tumors and the highly aggressive C1, C2 and C4 ovarian cancer signatures, and the basal-like breast cancer subtype. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer C3 signature. The borderline tumors, on the other hand, correlated significantly to the Luminal A breast cancer subtype. These findings remained when analyzed in a large, independent dataset. The data in this study link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, including an aggressive phenotype, frequent TP53 mutations and a high degree of genomic instability, and suggest that biomarkers and targeted therapies may overlap between these subsets of ovarian and breast cancers. Finally, the link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers. Total RNA obtained from serous ovarian adenocarcinomas, adenomas and borderline tumors. Gene expression profiling using Illumina's HT12 v4 bead arrays. Application of ovarian cancer molecular subtypes and intrinsic breast cancer subtypes using nearest centroid classification. KRAS and BRAF mutation analyses in the malignant and borderline tumors.

Dataset Information

The Impact of Stroma Admixture on Molecular Subtypes and Prognostic Gene Signatures in Serous Ovarian Cancer.

Background

Methods

Results

Conclusions

Impact

Publications

The Impact of Stroma Admixture on Molecular Subtypes and Prognostic Gene Signatures in Serous Ovarian Cancer.

Similar Datasets

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