Validating the impact of a molecular subtype in ovarian cancer on outcomes

TY - JOUR

T1 - Validating the impact of a molecular subtype in ovarian cancer on outcomes

T2 - a study of the OVCAD Consortium

AU - Pils, Dietmar

AU - Hager, Gudrun

AU - Tong, Dan

AU - Aust, Stefanie

AU - Heinze, Georg

AU - Kohl, Maria

AU - Schuster, Eva

AU - Wolf, Andrea

AU - Sehouli, Jalid

AU - Braicu, Ioana

AU - Vergote, Ignace

AU - Cadron, Isabelle

AU - Mahner, Sven

AU - Hofstetter, Gerda

AU - Speiser, Paul

AU - Zeillinger, Robert

N1 - © 2012 Japanese Cancer Association.

PY - 2012/7/1

Y1 - 2012/7/1

N2 - Most patients with epithelial ovarian cancer (EOC) are diagnosed at advanced stage and have a poor prognosis. However, a small proportion of these patients will survive, whereas others will die very quickly. Clinicopathological factors do not allow precise identification of these subgroups. Thus, we have validated a molecular subclassification as new prognostic factor in EOC. One hundred and ninety-four patients with Stage II-IV EOC were characterized by whole-genome expression profiling of tumor tissues and were classified using a published 112 gene set, derived from an International Federation of Gynecology and Obstetrics (FIGO) stage-directed supervised classification approach. The 194 tumor samples were classified into two subclasses comprising 95 (Subclass 1) and 99 (Subclass 2) tumors. All nine FIGO II tumors were grouped in Subclass 1 (P = 0.001). Subclass 2 (54% of advanced-stage tumors) was significantly correlated with peritoneal carcinomatosis and non-optimal debulking. Patients with Subclass 2 tumors had a worse overall survival for both serous and non-serous histological subtypes, as revealed by univariate analysis (hazard ratios [HR] of 3.17 and 17.11, respectively; P ≤ 0.001) and in models corrected for relevant clinicopathologic parameters (HR 2.87 and 12.42, respectively; P ≤ 0.023). Significance analysis of microarrays revealed 2082 genes that were differentially expressed in advanced-grade serous tumors of both subclasses and the focal adhesion pathway as the most deregulated pathway. In the present validation study, we have shown that, in advanced-stage serous ovarian cancer, two approximately equally large molecular subtypes exist, independent of classical clinocopathological parameters and presenting with highly different whole-genome expression profiles and a markedly different overall survival. Similar results were obtained in a small cohort of patients with non-serous tumors.

AB - Most patients with epithelial ovarian cancer (EOC) are diagnosed at advanced stage and have a poor prognosis. However, a small proportion of these patients will survive, whereas others will die very quickly. Clinicopathological factors do not allow precise identification of these subgroups. Thus, we have validated a molecular subclassification as new prognostic factor in EOC. One hundred and ninety-four patients with Stage II-IV EOC were characterized by whole-genome expression profiling of tumor tissues and were classified using a published 112 gene set, derived from an International Federation of Gynecology and Obstetrics (FIGO) stage-directed supervised classification approach. The 194 tumor samples were classified into two subclasses comprising 95 (Subclass 1) and 99 (Subclass 2) tumors. All nine FIGO II tumors were grouped in Subclass 1 (P = 0.001). Subclass 2 (54% of advanced-stage tumors) was significantly correlated with peritoneal carcinomatosis and non-optimal debulking. Patients with Subclass 2 tumors had a worse overall survival for both serous and non-serous histological subtypes, as revealed by univariate analysis (hazard ratios [HR] of 3.17 and 17.11, respectively; P ≤ 0.001) and in models corrected for relevant clinicopathologic parameters (HR 2.87 and 12.42, respectively; P ≤ 0.023). Significance analysis of microarrays revealed 2082 genes that were differentially expressed in advanced-grade serous tumors of both subclasses and the focal adhesion pathway as the most deregulated pathway. In the present validation study, we have shown that, in advanced-stage serous ovarian cancer, two approximately equally large molecular subtypes exist, independent of classical clinocopathological parameters and presenting with highly different whole-genome expression profiles and a markedly different overall survival. Similar results were obtained in a small cohort of patients with non-serous tumors.

KW - Adult

KW - European Union

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Kaplan-Meier Estimate

KW - Middle Aged

KW - Multivariate Analysis

KW - Neoplasm Grading

KW - Neoplasm Staging

KW - Neoplasms, Glandular and Epithelial

KW - Oligonucleotide Array Sequence Analysis

KW - Ovarian Neoplasms

KW - Prognosis

KW - Proportional Hazards Models

U2 - 10.1111/j.1349-7006.2012.02306.x

DO - 10.1111/j.1349-7006.2012.02306.x

M3 - SCORING: Journal article

C2 - 22497737

VL - 103

SP - 1334

EP - 1341

JO - CANCER SCI

JF - CANCER SCI

SN - 1347-9032

IS - 7

ER -