title: Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer.
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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Tuan Zea
authors.initials: TZ
authors.lastname: Tan
authors.forename: Qing Hao
authors.initials: QH
authors.lastname: Miow
authors.forename: Ruby Yun-Ju
authors.initials: RY
authors.lastname: Huang
authors.forename: Meng Kang
authors.initials: MK
authors.lastname: Wong
authors.forename: Jieru
authors.initials: J
authors.lastname: Ye
authors.forename: Jieying Amelia
authors.initials: JA
authors.lastname: Lau
authors.forename: Meng Chu
authors.initials: MC
authors.lastname: Wu
authors.forename: Luqman Hakim
authors.initials: LH
authors.lastname: Bin Abdul Hadi
authors.forename: Richie
authors.initials: R
authors.lastname: Soong
authors.forename: Mahesh
authors.initials: M
authors.lastname: Choolani
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.forename: Jahn M
authors.initials: JM
authors.lastname: Nesland
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Wang
authors.forename: Noriomi
authors.initials: N
authors.lastname: Matsumura
authors.forename: Masaki
authors.initials: M
authors.lastname: Mandai
authors.forename: Ikuo
authors.initials: I
authors.lastname: Konishi
authors.forename: Boon-Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chang
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mori
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008870:Microtubules / Q000473:pathology; D063213:N-Terminal Acetyltransferase E / Q000235:genetics; D063206:N-Terminal Acetyltransferases; D009375:Neoplasms, Glandular and Epithelial / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D010053:Ovary / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis
chemical_list: D008869:Microtubule-Associated Proteins; C401398:TUBGCP4 protein, human; D063213:N-Terminal Acetyltransferase E; D063206:N-Terminal Acetyltransferases; C522989:NAT10 protein, human
keywords: cell line model for subtype; functional genomic screen; molecular subtype; ovarian cancer; tubulin