The Impact of Stroma Admixture on Molecular Subtypes and Prognostic Gene Signatures in Serous Ovarian Cancer.
Journal
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
ISSN: 1538-7755
Titre abrégé: Cancer Epidemiol Biomarkers Prev
Pays: United States
ID NLM: 9200608
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
19
12
2018
revised:
26
04
2019
accepted:
06
12
2019
pubmed:
25
12
2019
medline:
20
1
2021
entrez:
25
12
2019
Statut:
ppublish
Résumé
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. 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. 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. 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. Single-cell analyses may be required to refine the molecular subtypes of high-grade serous ovarian cancer.
Sections du résumé
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.
Identifiants
pubmed: 31871106
pii: 1055-9965.EPI-18-1359
doi: 10.1158/1055-9965.EPI-18-1359
pmc: PMC7448721
mid: NIHMS1546628
doi:
Substances chimiques
Biomarkers, Tumor
0
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
509-519Subventions
Organisme : NCI NIH HHS
ID : P01 CA087969
Pays : United States
Organisme : NCI NIH HHS
ID : R03 CA191447
Pays : United States
Organisme : NIMHD NIH HHS
ID : G12 MD007599
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA180996
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA133057
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA220523
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA174206
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA148065
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA151118
Pays : United States
Organisme : NCI NIH HHS
ID : RC4 CA156551
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006516
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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