Research

Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer (EMBO Mol Med, May 2013)

Epithelial ovarian cancer (EOC) is hallmarked by a high degree of heterogeneity. To address this heterogeneity, a classification scheme was developed based on gene expression patterns of 1538 tumours. Five, biologically distinct subgroups — Epi-A, Epi-B, Mes, Stem-A and Stem-B — exhibited significantly distinct clinicopathological characteristics, deregulated pathways and patient prognoses, and were validated using independent datasets. To identify subtypespecific molecular targets, ovarian cancer cell lines representing these molecular subtypes were screened against a genome-wide shRNA library. Focusing on the poor-prognosis Stem-A subtype, we found that two genes involved in tubulin processing, TUBGCP4 and NAT10, were essential for cell growth, an observation supported by a pathway analysis that also predicted involvement of microtubulerelated processes. Furthermore, we observed that Stem-A cell lines were indeed more sensitive to inhibitors of tubulin polymerization, vincristine and vinorelbine, than the other subtypes. This subtyping offers new insights into the development of novel diagnostic and personalized treatment for EOC patients.

seiichi

Authors:

Tuan Zea Tan1Y, Qing Hao Miow1,2Y, Ruby Yun-Ju Huang1,3Y, Meng Kang Wong1, Jieru Ye1, Jieying Amelia Lau1, Meng Chu Wu1, Luqman Hakim Bin Abdul Hadi1, Richie Soong1, Mahesh Choolani3, Ben Davidson4,5, Jahn M. Nesland4,5, Ling-Zhi Wang1,6, Noriomi Matsumura7, Masaki Mandai7, Ikuo Konishi7, Boon-Cher Goh1,6,8, Jeffrey T. Chang9, Jean Paul Thiery1,10,11*, Seiichi Mori1,11,12**,Z

1Cancer Science Institute of Singapore, National University of Singapore, Singapore
2NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
3Department of Obstetrics and Gynecology, National University Health System, Singapore
4Division of Pathology, Norwegian Radium Hospital Oslo University Hospital, Oslo, Norway
5Faculty of Medicine, University of Oslo, Institute of Clinical Medicine, Oslo, Norway
6Department of Pharmacology, National University of Singapore, Singapore
7Department of Obstetrics and Gynecology, Kyoto University, Kyoto, Japan
8Department of Hematology and Oncology, National University Health System, Singapore
9Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, TX, USA
10Institute of Molecular and Cell Biology, ASTAR (Agency for Science, Technology and Research), Singapore
11Department of Biochemistry, National University of Singapore, Singapore
12Division of Cancer Genomics, Cancer Institute of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, Japan

*Corresponding author: Tel: þ65 6516 3241/42; þ65 91472036;
Fax: þ65 6779 1453;
E-mail: jpthiery[at]imcb.a-star.edu.sg
**Corresponding author: Tel: þ81 3 3570 0450; Fax: þ81 3 3570 0454;
E-mail: seiichi.mori[at]jfcr.or.jp
YThese authors contributing equally to this work.
ZPresent Address: Division of Cancer Genomics, Cancer Institute of Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan

Link to PubMed