Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome.
OBJECTIVE
The study aim to identify novel molecular subtypes of ovarian cancer by gene expression profiling with linkage to clinical and pathologic features.


METHODS
Microarray gene expression profiling was done on 285 serous and endometrioid tumors of the ovary, peritoneum, and fallopian tube. K-means clustering was applied to identify robust molecular subtypes. Statistical analysis identified differentially expressed genes, pathways, and gene ontologies. Laser capture microdissection, pathology review, and immunohistochemistry validated the array-based findings. Patient survival within k-means groups was evaluated using Cox proportional hazards models. Class prediction validated k-means groups in an independent dataset. A semisupervised survival analysis of the array data was used to compare against unsupervised clustering results.


RESULTS
Optimal clustering of array data identified six molecular subtypes. Two subtypes represented predominantly serous low malignant potential and low-grade endometrioid subtypes, respectively. The remaining four subtypes represented higher grade and advanced stage cancers of serous and endometrioid morphology. A novel subtype of high-grade serous cancers reflected a mesenchymal cell type, characterized by overexpression of N-cadherin and P-cadherin and low expression of differentiation markers, including CA125 and MUC1. A poor prognosis subtype was defined by a reactive stroma gene expression signature, correlating with extensive desmoplasia in such samples. A similar poor prognosis signature could be found using a semisupervised analysis. Each subtype displayed distinct levels and patterns of immune cell infiltration. Class prediction identified similar subtypes in an independent ovarian dataset with similar prognostic trends.


CONCLUSIONS
Gene expression profiling identified molecular subtypes of ovarian cancer of biological and clinical importance.
Tothill
Richard W
RW
Peter MacCallum Cancer Center, University of Melbourne, Melbourne, Australia.
Tinker
Anna V
AV
George
Joshy
J
Brown
Robert
R
Fox
Stephen B
SB
Lade
Stephen
S
Johnson
Daryl S
DS
Trivett
Melanie K
MK
Etemadmoghadam
Dariush
D
Locandro
Bianca
B
Traficante
Nadia
N
Fereday
Sian
S
Hung
Jillian A
JA
Chiew
Yoke-Eng
YE
Haviv
Izhak
I
Gertig
Dorota
D
DeFazio
Anna
A
Bowtell
David D L
DD
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D007834:Lasers; D042282:Microdissection; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor