The 5'-end transitional CpGs between the CpG islands and retroelements are hypomethylated in association with loss of heterozygosity in gastric cancers.
BACKGROUND
A loss of heterozygosity (LOH) represents a unilateral chromosomal loss that reduces the dose of highly repetitive Alu, L1, and LTR retroelements. The aim of this study was to determine if the LOH events can affect the spread of retroelement methylation in the 5'-end transitional area between the CpG islands and their nearest retroelements.


METHODS
The 5'-transitional area of all human genes (22,297) was measured according to the nearest retroelements to the transcription start sites. For 50 gastric cancer specimens, the level of LOH events on eight cancer-associated chromosomes was estimated using the microsatellite markers, and the 5'-transitional CpGs of 20 selected genes were examined by methylation analysis using the bisulfite-modified DNA.


RESULTS
The extent of the transitional area was significantly shorter with the nearest Alu elements than with the nearest L1 and LTR elements, as well as in the extragenic regions containing a higher density of retroelements than in the intragenic regions. The CpG islands neighbouring a high density of Alu elements were consistently hypomethylated in both normal and tumor tissues. The 5'-transitional methylated CpG sites bordered by a low density of Alu elements or the L1 and LTR elements were hypomethylated more frequently in the high-level LOH cases than in the low-level LOH cases.


CONCLUSIONS
The 5'-transitional methylated CpG sites not completely protected by the Alu elements were hypomethylated in association with LOH events in gastric cancers. This suggests that an irreversible unbalanced decrease in the genomic dose reduces the spread of L1 methylation in the 5'-end regions of genes.
Kim
Young-Ho
YH
Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea. youngho5@hanmail.net
Hong
Seung-Jin
SJ
Jung
Yu-Chae
YC
Kim
Sung-Ja
SJ
Seo
Eun-Joo
EJ
Choi
Sang-Wook
SW
Rhyu
Mun-Gan
MG
D024506:5' Flanking Region / Q000235:genetics*; D000368:Aged; D020087:Alu Elements; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics* / Q000302:isolation & purification; D004303:Dosage Compensation, Genetic; D044127:Epigenesis, Genetic; D005260:Female; D005753:Gastric Mucosa / Q000737:chemistry; D018628:Gene Dosage; D006570:Heterochromatin / Q000235:genetics; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D018626:Retroelements; D013274:Stomach Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D020079:Terminal Repeat Sequences
D004273:DNA, Neoplasm; D006570:Heterochromatin; D018626:Retroelements