演題抄録

International Symposium

開催概要
開催回
第53回・2015年・京都
 

Integrated analysis of single nucleotide variants and copy number variants in ovarian clear cell adenocarcinoma

演題番号 : IS2-2

[筆頭演者]
Matsumura Noriomi:1 
[共同演者]
Murkami Ryuusuke:1、Higasa Koichiro:2、Tsutsumi Takanobu:2、Brown J. B.:3、Hamanishi Junzo:1、Yamaguchi Ken:1、Abiko Kaoru:1、Baba Tsukasa:1、Koshiyama Masafumi:1、Yamada Ryo:2、Matsuda Fumihiko:2、Okuno Yasushi:3、Konishi Ikuo:1

1:Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University、2:Center for Genomic Medicine, Graduate School of Medicine, Kyoto University、3:Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University

 

Recent advances in sequencing technology have identified cancer-related single nucleotide variants (SNVs) and copy number variants (CNVs). Ovarian clear cell carcinoma (OCCC), a chemoresistant subtype, accounts for 20% of ovarian cancer in Japan, which ratio is four times as high as that in the Western countries. In this study, we conducted an exome sequencing of 39 OCCC tissues following approval of an ethics committee and written consent of patients. In addition, we used a dataset of exome sequence of lymphocytes from 1,208 apparently normal Japanese. GSE58342, a publicly available SNP dataset of OCCC, was also used for external validation of the CNV data.
We identified SNVs of 340 genes, which met the following criteria; (1) amino acid changes, (2) absence in the 1,208 normal Japanese, and (3) existence in at least 2 OCCC tumors. These genes included oncogenes, such as PIK3CA (49%), PPP2R1A (10%), KRAS (7%), and tumor suppressor genes, such as ARID1A (62%), MLL3 (15%), ARID1B (10%), and PTEN (5%). Protein-protein interaction network analysis revealed "cell proliferation", "DNA repair", and "chromatin remodeling" pathways were enriched in the 340 genes.
Next, we conducted a CNV analysis. Amplified locus included 8q (67%), 20q (54%) and 17q (46%). Deleted locus included 13q (28%), 9p (21%), and 18q (21%). The CNV frequency histogram was very reproducible compared with GSE58342 data. Amplification of 17q21-24 was frequent in relapsed cases (FDR q<0.05), which amplification was an independent poor prognostic factor (p<0.05). In GSE58342 data, amplification of this region was again more frequent in relapsed cases (FDR q<0.05).
Integrated analysis of SNVs and CNVs found KRAS-PIK3CA-AKT1-PTEN (85%), MYC-CDK2-CDK4-RB1 (79%), and SWI/SNF complex (59%) pathways were deregulated.
In conclusion, we conducted exome sequencing of OCCC and identified novel mutated genes, prognostically relevant CNVs, and targetable pathways frequently deregulated through DNA alterations.

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