OBJECTIVE: Two chromosomal instability (CIN) pathways are described in glioblastoma multiforme (GBM), type 1 and type 2, which can be observed in up to 70% of the cases. Microsatellite instability (MSI) plays a pathogenic role in sporadic cancers such as colon, gastric and endometrial carcinomas with deficient mismatch repair (MMR). We aimed to perform a comprehensive analysis of the relationship between CIN and MSI mechanisms in sporadic glioblastomas. METHODS: 129 GBMs were examined (109 newly diagnosed and 20 relapses) investigating MSI, immunohistochemical expression of MMR proteins as well as sequencing and promoter methylation of hMLH1. We characterized the molecular changes frequently correlated with CIN in MSI+ GBMs and compared them with 26 microsatellite-stable tumors. RESULTS: Low-level MSI was observed in 11 of 129 (8.5%) cases and was higher in relapses than in primary GBMs (25 vs. 5.5%, p = 0.027). High-level MSI was not found in any case. A deficient expression of MLH1 and PMS2 without hMLH1 inactivation was observed only in one giant cell GBM. 55% of the MSI+ GBMs showed a profile which did not correspond to one of the known CIN pathways. An inverse association was observed between MSI and mutations of both p53 and PTEN. CONCLUSIONS: Our data suggest that CIN and MSI contribute to the genomic instability in GBMs via independent pathways. Since MSI was significantly more frequent in relapses, it might play a role in the malignant progression of GBM.
OBJECTIVE: Two chromosomal instability (CIN) pathways are described in glioblastoma multiforme (GBM), type 1 and type 2, which can be observed in up to 70% of the cases. Microsatellite instability (MSI) plays a pathogenic role in sporadic cancers such as colon, gastric and endometrial carcinomas with deficient mismatch repair (MMR). We aimed to perform a comprehensive analysis of the relationship between CIN and MSI mechanisms in sporadic glioblastomas. METHODS: 129 GBMs were examined (109 newly diagnosed and 20 relapses) investigating MSI, immunohistochemical expression of MMR proteins as well as sequencing and promoter methylation of hMLH1. We characterized the molecular changes frequently correlated with CIN in MSI+ GBMs and compared them with 26 microsatellite-stable tumors. RESULTS: Low-level MSI was observed in 11 of 129 (8.5%) cases and was higher in relapses than in primary GBMs (25 vs. 5.5%, p = 0.027). High-level MSI was not found in any case. A deficient expression of MLH1 and PMS2 without hMLH1 inactivation was observed only in one giant cell GBM. 55% of the MSI+ GBMs showed a profile which did not correspond to one of the known CIN pathways. An inverse association was observed between MSI and mutations of both p53 and PTEN. CONCLUSIONS: Our data suggest that CIN and MSI contribute to the genomic instability in GBMs via independent pathways. Since MSI was significantly more frequent in relapses, it might play a role in the malignant progression of GBM.
Authors: Ian F Pollack; Ronald L Hamilton; Robert W Sobol; Marina N Nikiforova; Yuri E Nikiforov; Maureen A Lyons-Weiler; William A LaFramboise; Peter C Burger; Daniel J Brat; Marc K Rosenblum; Floyd H Gilles; Allan J Yates; Tianni Zhou; Kenneth J Cohen; Jonathan L Finlay; Regina I Jakacki Journal: Pediatr Blood Cancer Date: 2010-12-01 Impact factor: 3.167
Authors: Daniel P Cahill; Kymberly K Levine; Rebecca A Betensky; Patrick J Codd; Candice A Romany; Linsey B Reavie; Tracy T Batchelor; P Andrew Futreal; Michael R Stratton; William T Curry; A John Iafrate; David N Louis Journal: Clin Cancer Res Date: 2007-04-01 Impact factor: 12.531
Authors: Chul-Kee Park; Ja Eun Kim; Ji Young Kim; Sang Woo Song; Jin Wook Kim; Seung Hong Choi; Tae Min Kim; Se-Hoon Lee; Il Han Kim; Sung-Hye Park Journal: Transl Oncol Date: 2012-10-01 Impact factor: 4.243
Authors: Jacky T Yeung; Ronald L Hamilton; Koji Ohnishi; Maki Ikeura; Douglas M Potter; Marina N Nikiforova; Soldano Ferrone; Regina I Jakacki; Ian F Pollack; Hideho Okada Journal: Clin Cancer Res Date: 2013-02-11 Impact factor: 12.531