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Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer

2013; Springer Nature; Volume: 5; Issue: 7 Linguagem: Inglês

10.1002/emmm.201201823

1757-4684

Tuan Zea Tan, Qing Hao Miow, Ruby Yun‐Ju Huang, M. K. Wong, Jieru Ye, Jieying Amelia Lau, Meng Wu, Luqman Hakim Bin Abdul Hadi, Richie Soong, Mahesh Choolani, Ben Davidson, Jahn M. Nesland, Lingzhi Wang, Noriomi Matsumura, Masaki Mandai, Ikuo Konishi, Boon Cher Goh, Jeffrey T. Chang, Jean Paul Thiery, Seiichi Mori,

Cancer-related molecular mechanisms research

Abstract 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 subtype‐specific 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 microtubule‐related 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.