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

PLoS One. 2015 Jun 4;10(6):e0128066. doi: 10.1371/journal.pone.0128066. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Clear Cell / genetics*
  • Adenocarcinoma, Clear Cell / pathology*
  • Chromosomal Instability / genetics
  • Chromosome Aberrations*
  • Cluster Analysis
  • DNA Copy Number Variations / genetics
  • Female
  • Gene Dosage*
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor
  • Genotype
  • Humans
  • Loss of Heterozygosity
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology*
  • Polymorphism, Single Nucleotide / genetics
  • Prognosis
  • Treatment Outcome

Grants and funding

Grant Support: Ministry of Education, Science, Sports, and Culture Grant Number: Scientific Research (S) 24221011 (to H. Aburatani); the Grant-in-aid for Scientific Research (C), Grant Number 26462515 (to K. Oda), and the Grant-in-aid for Young Scientific Research (B), Grant Number 25861473 (to Y. Uehara) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and a research program grant (to T. Yano) from the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) Grant Number 11114014, Ministry of Education, Culture, Sports, Science and Technology of Japan.