A novel correlation between LINE-1 hypomethylation and the malignancy of gastrointestinal stromal tumors.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
First Department of Internal Medicine, Sapporo Medical University, Japan.
Shinichi
S
Igarashi
Hiromu
H
Suzuki
Takeshi
T
Niinuma
Haruo
H
Shimizu
Masanori
M
Nojima
Hiroyuki
H
Iwaki
Takayuki
T
Nobuoka
Toshirou
T
Nishida
Yasuaki
Y
Miyazaki
Hiroyuki
H
Takamaru
Eiichiro
E
Yamamoto
Hiroyuki
H
Yamamoto
Takashi
T
Tokino
Tadashi
T
Hasegawa
Koichi
K
Hirata
Kohzoh
K
Imai
Minoru
M
Toyota
Yasuhisa
Y
Shinomura
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020087:Alu Elements / Q000235:genetics; D002869:Chromosome Aberrations / Q000706:statistics & numerical data; D055028:Comparative Genomic Hybridization; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000502:physiology; D018450:Disease Progression; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged