title: Integrated copy number and expression analysis identifies profiles of whole-arm chromosomal alterations and subgroups with favorable outcome in ovarian clear cell carcinomas.
abstract: Ovarian clear cell carcinoma (CCC) is generally associated with chemoresistance and poor clinical outcome, even with early diagnosis; whereas high-grade serous carcinomas (SCs) and endometrioid carcinomas (ECs) are commonly chemosensitive at advanced stages. Although an integrated genomic analysis of SC has been performed, conclusive views on copy number and expression profiles for CCC are still limited. In this study, we performed single nucleotide polymorphism analysis with 57 epithelial ovarian cancers (31 CCCs, 14 SCs, and 12 ECs) and microarray expression analysis with 55 cancers (25 CCCs, 16 SCs, and 14 ECs). We then evaluated PIK3CA mutations and ARID1A expression in CCCs. SNP array analysis classified 13% of CCCs into a cluster with high frequency and focal range of copy number alterations (CNAs), significantly lower than for SCs (93%, P < 0.01) and ECs (50%, P = 0.017). The ratio of whole-arm to all CNAs was higher in CCCs (46.9%) than SCs (21.7%; P < 0.0001). SCs with loss of heterozygosity (LOH) of BRCA1 (85%) also had LOH of NF1 and TP53, and LOH of BRCA2 (62%) coexisted with LOH of RB1 and TP53. Microarray analysis classified CCCs into three clusters. One cluster (CCC-2, n = 10) showed more favorable prognosis than the CCC-1 and CCC-3 clusters (P = 0.041). Coexistent alterations of PIK3CA and ARID1A were more common in CCC-1 and CCC-3 (7/11, 64%) than in CCC-2 (0/10, 0%; P < 0.01). Being in cluster CCC-2 was an independent favorable prognostic factor in CCC. In conclusion, CCC was characterized by a high ratio of whole-arm CNAs; whereas CNAs in SC were mainly focal, but preferentially caused LOH of well-known tumor suppressor genes. As such, expression profiles might be useful for sub-classification of CCC, and might provide useful information on prognosis.
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Uehara
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Oda
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Koso
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Asada
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenbun
authors.initials: K
authors.lastname: Sone
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Kurikawa
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Chinami
authors.initials: C
authors.lastname: Makii
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Otoe
authors.initials: O
authors.lastname: Hagiwara
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Tanikawa
authors.affiliation: Department of Pathology, The University of Tokyo, Tokyo, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Maeda
authors.affiliation: Department of Obstetrics and Gynecology, Saitama Medical University International Medical Center, Saitama, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Obstetrics and Gynecology, Teikyo University International, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Wada-Hiraike
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Kawana
authors.affiliation: Department of Pathology, The University of Tokyo, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: Department of Obstetrics and Gynecology, Saitama Medical University International Medical Center, Saitama, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yano
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osuga
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics* / Q000473:pathology*; D043171:Chromosomal Instability / Q000235:genetics; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D016896:Treatment Outcome