Open AccessAlternative lengthening of telomeres frequently occurs in mismatch repair system‐deficient gastric carcinoma
Author(s) -
Omori Yasuhiro,
Nakayama Fumihito,
Li Dong,
Kanemitsu Kiyonori,
Semba Shuho,
Ito Akihiko,
Yokozaki Hiroshi
Publication year - 2009
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2008.01063.x
Subject(s) - telomere , telomerase , microsatellite instability , telomerase reverse transcriptase , biology , cancer research , ribonucleoprotein , in situ hybridization , carcinogenesis , cancer , dna , genetics , microsatellite , gene , rna , allele , gene expression
Maintenance of telomeric ends by the telomerase ribonucleoprotein complex or the telomerase‐independent alternative lengthening of telomeres is necessary for the immortalization of human cells. The significance of alternative lengthening of telomeres has been suggested in DNA mismatch repair system‐deficient cells; however, much remains unknown in human malignancies. In this study, we investigated the telomere maintenance mechanism in gastric carcinoma. In formalin‐fixed and paraffin‐embedded sections of the high frequency of microsatellite instability (MSI‐H) and non‐MSI‐H gastric carcinomas, there was no difference in telomere length monitored by telomere intensity ratio using telomere‐fluorescent in situ hybridization. Immunoreactivity of hTERT, the catalytic subunit of telomerase, was detected in 48% of MSI‐H gastric carcinomas. The frequency was significantly lower than that in non‐MSI‐H gastric carcinomas (86%, P = 0.02). Conversely, the number of the alternative lengthening of telomeres‐associated promyelocytic leukemia bodies (APBs) detected by combined promyelocytic leukemia immunofluorescence and telomere‐fluorescent in situ hybridization was statistically higher (57%) in the MSI‐H gastric carcinomas compared to that in non‐MSI‐H gastric carcinomas (19%, P = 0.026). The cases with hTERT(+)APBs(–) were more frequent in non‐MSI‐H gastric carcinomas (76%) than in MSI‐H gastric carcinomas (24%), and the cases with hTERT(–)APBs(+) were more frequent in MSI‐H gastric carcinomas (33%) than in non‐MSI‐H gastric carcinomas (10%). These results suggest that alternative lengthening of telomeres‐mediated telomere maintenance plays an important role for microsatellite instability‐mediated stomach carcinogenesis, as well as the telomerase ribonucleoprotein complex, although the incidence of MSI‐H is low. Defects of the mismatch repair system may lead to homeologous recombination of telomeric ends for the telomerase‐independent telomere maintenance in gastric carcinomas. ( Cancer Sci 2009; 100: 413–418)