Alternative lengthening of telomeres frequently occurs in mismatch repair system‐deficient gastric carcinoma

Abstract

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.