Detection of frequent genomic deletions in malignant mesothelioma cells

2010 Fiscal Year Final Research Report

• Project/Area Number: 20590590
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Hyogo Medical University
• Principal Investigator: TAMAOKI Tomoko (HASHIMOTO Tomoko) 兵庫医科大学, 医学部, 教授 (10172868)
• Co-Investigator(Kenkyū-buntansha): TSUJIMURA Toru 兵庫医科大学, 医学部, 教授 (20227408) ; NAKANO Takashi 兵庫医科大学, 医学部, 教授 (10155781) ; FUKUOKA Kazuya 兵庫医科大学, 医学部, 准教授 (80305721) ; MORINAGA Tomonori 兵庫医科大学, 医学部, 助教 (10351818) ; YOSHIKAWA Reigetsu 兵庫医科大学, 医学部, 助教 (90319864) ; SAITO Yuko 兵庫医科大学, 医学部, 講師 (00254350) ; YOSHIKAWA Yoshie 兵庫医科大学, 医学部, 助教 (10566673)
• Project Period (FY): 2008 – 2010
• Keywords: 悪性中皮腫 / 上皮型中皮腫 / ゲノム解析 / CDKN2A・2B / セマフォリン / VEGF / BAP1

Research Abstract

Malignant mesothelioma(MM) is an asbestos-related tumor. Array-based CGH was performed using MM primary-cultured cells established in Hyogo College of Medicine(HCM). In HCM-MM cell samples, frequent deletions were detected in 1p, 3p21, 4q, 9p21, 16p13 and 22q. We also used ATCC and Riken MM cells. All 21 MM cells showed homozygous deletions in the 9p21 region carrying the CDKN2A/p16 and CDKN2B/p15 genes. Homozygous or heterozygous deletions in the 22q region carrying the NF2 gene were detected in 80% of HCC-MM cells, and deletions in 3p21.1-21.31 in 50%. We focused on the 3p21 region because it was specific to the epithelioid type. Since 3p21.1 and 3p21.31 regions contain Semaphorin family genes that inhibit VEGF activity, we analyzed gene expression profiles and found that lower expression of several SEMA genes and higher expression of VEGFA in epithelioid MMs than in Met5a, a normal mesothelial cell line, suggesting that VEGFA biological activity may be higher in epithelioid MMs. Genome alterations of BAP1, located in 3p21.1, was detected in 15 of 16 epithelioid MMs ; biallelic deletions or monoallelic deletions with or without mutations. Immunostaining with anti-BAP1 antibody showed negative nuclear staining in most of epithelioid MMs. These BAP1 mutations and deletions were somatic, since no germinal mutations were detected. These results showed that BAP1 mutation plays a significant role in the pathogenesis of epithelioid MMs.

Research Products

• [Journal Article] Frequent inactivation of BAP1 gene in epithelioid-type malignant mesothelioma (2012)
  • Author(s): Yoshikawa Y, Sato A, Tsujimura T, Emi M, Morinaga T, Fukuoka K, Yamada S, Murakami A, Kondo N, Matsumoto S, Okumura Y, Tanaka F, Hasegawa S, Nakano T, Hashimoto-Tamaoki T.
  • Journal Title: Cancer Sci
• [Journal Article] Frequent deltion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells (2011)
  • Author(s): Yoshikawa Y, Sato A, Tsujimura T, Morinaga T, Fukuoka K, Yamada S, Murakami A, Kondo N, Matsumoto S, Okumura Y, Tanaka F, Hasegawa S, Hashimoto-Tamaoki T, Nakano T.
  • Journal Title: Int J Oncol Volume: 39(6) Pages: 1365-74
• [Presentation] Frequent deletions in 3p21.1region in malignant mesothelioma cell lines established from Japanese patients(IMIG2010) (2010)
  • Author(s): Yoshikawa Y, Nakano Y, Sato A, Fukuoka K, Murakami A, Yamada S, Morinaga T, Tsujimura T, Hashimoto-Tamaoki T.
  • Place of Presentation: Kyoto
  • Year and Date: 20100831-0903
• [Presentation] 悪性中皮腫におけるBAP1(BRCA1 associated protein 1)遺伝子の高頻度欠失 (2010)
  • Author(s): 吉川良恵, 森永伴法, 佐藤鮎子, 福岡和也, 辻村亨, 玉置(橋本)知子, 中野孝司
  • Organizer: 第69回日本癌学会学術総会(JCA2010)
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-24