Integrated copy number and expression analysis identifies profiles of whole-arm chromosomal alterations and subgroups with favorable outcome in ovarian clear cell carcinomas.

Yuriko Uehara,Reiko Kurikawa,Kei Kawana,Daichi Maeda,Tetsu Yano,Yutaka Osuga,Takahiro Koso,Hiroyuki Aburatani,Michihiro Tanikawa,Shingo Tsuji,Kosei Hasegawa,Otoe Hagiwara,Osamu Wada-Hiraike,Shunsuke Nakagawa,Masashi Fukayama,Tomoyuki Fujii,Keiichi Fujiwara,Kenbun Sone,Yuji Ikeda,Chinami Makii,Katsutoshi Oda,Kenichi Asada ,Shozo Yamamoto

doi:10.1371/journal.pone.0128066

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.

Highlights

Epithelial ovarian cancer is a leading cause of death resulting from gynecological malignancies, and is characterized by high recurrence and poor survival rates [1]
Representative single-nucleotide polymorphism (SNP) array “karyograms” of each tumor are shown in S1 Fig. The Y-axis values for loss of heterozygosity (LOH) in the karyograms of SNP array were comparable among the samples tested, suggesting that the tumor ratio in this study was suitable for analysis (S1 Fig)
We focused on relationships between chromosomal instability (CIN) status and histological subtypes (CCC, endometrioid carcinomas (ECs), and serous carcinoma (SC))

Summary

Introduction

Epithelial ovarian cancer is a leading cause of death resulting from gynecological malignancies, and is characterized by high recurrence and poor survival rates [1]. Genome-wide copy number alterations (CNAs) and gene expression profiles for ovarian tumors have been constructed from analyses consisting mainly of SC tumor samples, as high-grade SC is the most common histological subtype and accounts for approximately 60–70% of all the ovarian cancers [2]. High-grade SC is characterized by highly prevalent TP53 mutations, statistically recurrent mutations of other tumor suppressor genes (NF1, RB1, and BRCA1/2), and CNAs at specific loci. Copy number loss of BRCA2 and RB1, as well as TP53 and BRCA1 CNAs, were potentially correlated with each other in BRCA-mutated ovarian cancers [5]. The contribution of BRCA copy number loss and its correlation with CNAs in other tumor-suppressor genes in various types of (mainly sporadic) ovarian cancer remain unclear

Methods

Results

Conclusion