A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

• Published in: Clinical cancer research 2010-11, Vol.16 (21), p.5114-5123
• Main Authors: IGARASHI, Shinichi, SUZUKI, Hiromu, YAMAMOTO, Eiichiro, YAMAMOTO, Hiroyuki, TOKINO, Takashi, HASEGAWA, Tadashi, HIRATA, Koichi, IMAI, Kohzoh, TOYOTA, Minoru, SHINOMURA, Yasuhisa, NIINUMA, Takeshi, SHIMIZU, Haruo, NOJIMA, Masanori, IWAKI, Hiroyuki, NOBUOKA, Takayuki, NISHIDA, Toshirou, MIYAZAKI, Yasuaki, TAKAMARU, Hiroyuki
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Alu Elements - genetics; Antineoplastic agents; Biological and medical sciences; Chromosome Aberrations - statistics & numerical data; Comparative Genomic Hybridization; CpG Islands - genetics; Disease Progression; DNA Methylation - physiology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal Stromal Tumors - genetics; Gastrointestinal Stromal Tumors - pathology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Long Interspersed Nucleotide Elements - genetics; Male; Medical sciences; Microarray Analysis; Middle Aged; Pharmacology. Drug treatments; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-10-0581

Gastrointestinal stromal tumors (GIST) are the most important mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs exhibit activating mutations of KIT or PDGFRA, but epigenetic alteration of GISTs is largely unknown. In this study, we aimed to clarify the involvement of DNA methylation in GIST malignancy. A total of 106 GIST specimens were studied. Levels of LINE-1 methylation were analyzed using bisulfite pyrosequencing. In addition, methylation of three other repetitive sequences (Alu Yb8, Satellite-α, and NBL2) was similarly analyzed, and CpG island hypermethylation was analyzed using MethyLight. Array-based comparative genomic hybridization (array CGH) was carried out in 25 GIST specimens. LINE-1 hypomethylation was significantly correlated with risk, and high-risk GISTs exhibited significantly lower levels of LINE-1 methylation than low-risk (61.3% versus 53.2%; P = 0.001) or intermediate-risk GISTs (60.8% versus 53.2%; P = 0.002). Hypomethylation of Satellite-α and NBL2 was also observed in high-risk GISTs. By contrast, promoter hypermethylation was relatively infrequent (CDH1, 11.2%; MLH1, 9.8%; SFRP1, 1.2%; SFRP2, 11.0%; CHFR, 9.8%; APC, 6.1%; CDKN2A, 0%; RASSF1A, 0%; RASSF2, 0%) and did not correlate with LINE-1 methylation or risk. Array CGH analysis revealed a significant correlation between LINE-1 hypomethylation and chromosomal aberrations. Our data suggest that LINE-1 hypomethylation correlates significantly with the aggressiveness of GISTs and that LINE-1 methylation could be a useful marker for risk assessment. Hypomethylation may increase the malignant potential of GISTs by inducing accumulation of chromosomal aberrations.