title: Establishment of a Novel Histopathological Classification of High-Grade Serous Ovarian Carcinoma Correlated with Prognostically Distinct Gene Expression Subtypes.
abstract: Recently, The Cancer Genome Atlas data revealed four molecular subtypes of high-grade serous ovarian carcinoma (HGSOC) exhibiting distinct prognoses. We developed four novel HGSOC histopathological subtypes by focusing on tumor microenvironment: mesenchymal transition, defined by a remarkable desmoplastic reaction; immune reactive by lymphocytes infiltrating the tumor; solid and proliferative by a solid growth pattern; and papilloglandular by a papillary architecture. Unsupervised hierarchical clustering revealed four clusters correlated with histopathological subtypes in both Kyoto and Niigata HGSOC transcriptome data sets (P < 0.001). Gene set enrichment analysis revealed pathways enriched in our histopathological classification significantly overlapped with the four molecular subtypes: mesenchymal, immunoreactive, proliferative, and differentiated (P < 0.0001, respectively). In 132 HGSOC cases, progression-free survival and overall survival were best in the immune reactive, whereas overall survival was worst in the mesenchymal transition (P < 0.001, respectively), findings reproduced in 89 validation cases (P < 0.05, respectively). The CLOVAR_MES_UP single-sample gene set enrichment analysis scores representing the mesenchymal molecular subtype were higher in paclitaxel responders than nonresponders (P = 0.002) in the GSE15622 data set. Taxane-containing regimens improved survival of cases with high MES_UP scores compared with nontaxane regimens (P < 0.001) in the GSE9891 data set. Our novel histopathological classification of HGSOC correlates with distinct prognostic transcriptome subtypes. The mesenchymal transition subtype might be particularly sensitive to taxane.
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Murakami
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: noriomi@kuhp.kyoto-u.ac.jp.
authors.forename: Noriomi
authors.initials: N
authors.lastname: Matsumura
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mandai
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yoshihara
authors.affiliation: Department of Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanabe
authors.affiliation: Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Nakai
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanoi
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Abiko
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Junzo
authors.initials: J
authors.lastname: Hamanishi
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Baba
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Koshiyama
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Enomoto
authors.affiliation: Department of Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Aikou
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
authors.affiliation: Division of Cancer Genomics, Cancer Institute of Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mori
authors.affiliation: Department of Diagnostic Pathology, Kumamoto University Hospital, Kumamoto, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Mikami
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Minamiguchi
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Konishi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D049109:Cell Proliferation / Q000502:physiology; D018284:Cystadenocarcinoma, Serous / Q000145:classification / Q000401:mortality / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008875:Middle Aged; D015588:Observer Variation; D010051:Ovarian Neoplasms / Q000145:classification / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents