Microsatellite instability and the PTEN1 gene mutation in a subset of early onset gliomas carrying germline mutation or promoter methylation of the hMLH1 gene

Genetic Instability in Paediatric and Adult Brain Tumours

“…Importantly, the methodologies for determining MSI have been highly diverse, making it difficult to draw accurate conclusions (Table 4). To clarify the role of MSI in paediatric versus adult malignant brain tumours, our group has used a highly sensitive and robust panel of MSI markers and studied series of high-grade glioma and medulloblastoma of adult and paediatric samples for the presence of MSI (Viana-Pereira et al, 2009, 2011 gliomas, the frequency of MSI was significantly higher in paediatric than adult tumours (Viana-Pereira et al, 2011), reflecting the bulk of the previously published data (Alonso et al, 2001;Cheng et al, 1999;Kanamori et al, 2000;Leung et al, 1998;Martinez et al, 2005). On the other hand, in medulloblastomas, no difference was observed in MSI frequency between adult and paediatric tumours, suggesting that the presence of MSI in these tumours is not age-related (Viana-Pereira et al, 2009).…”

“…Previous studies have established MSI frequencies in gliomas using polynucleotide markers only, with frequencies ranging from 0 to 37% (Amariglio et al, 1995;Dams et al, 1995;Izumoto et al, 1997;Sobrido et al, 2000). Including both mononucleotide and polynucleotides repeat markers did not improve consistency, with contrasting results varying between 0 and 44% in paediatric gliomas cohorts or between 0 and 18% in adult tumours (Cheng et al, 1999;Kanamori et al, 2000;Leung et al, 1998;Martinez et al, 2005;Pollack et al, 2010b). Using mononucleotides only also provided contradictory results of 0 to 27% MSI in paediatric gliomas (Alonso et al, 2001;Eckert et al, 2007;Vladimirova et al, 2007).…”

“…Moreover, we have observed that both MSI-positive medulloblastoma and highgrade glioma presented small length alterations within the microsatellites and hypothesise that this can also contribute for the high variation frequency of MSI in brain tumours reported in the literature (Alonso et al, 2001;Amariglio et al, 1995;Cheng et al, 1999;Dams et al, 1995;Eckert et al, 2007;Izumoto et al, 1997;Kanamori et al, 2000;Leung et al, 1998;Martinez et al, 2005;Sobrido et al, 2000;Vladimirova et al, 2007). Importantly, the MSI-positive paediatric high-grade glioma mostly presented a stable genomic profile at the chromosomal level, even if microsatellite and chromosomal instability were not mutually exclusive.…”

“…Previous studies have evaluated the presence of MSI in brain tumours, particularly in gliomas, while in medulloblastomas MSI status has not been properly addressed. Reports in the literature describe the absence or rare incidence of MSI in adult patients, while in children results have been contradictory, with reported frequencies in paediatric gliomas varying between 0 and 44% (Alonso et al, 2001;Amariglio et al, 1995;Cheng et al, 1999;Dams et al, 1995;Eckert et al, 2007;Izumoto et al, 1997;Kanamori et al, 2000;Leung et al, 1998;Martinez et al, 2005;Sobrido et al, 2000;Vladimirova et al, 2007). Importantly, the methodologies for determining MSI have been highly diverse, making it difficult to draw accurate conclusions (Table 4).…”

Biallelic germline mutations of mismatch‐repair genes

“…In addition, MSI was detected previously in pediatric brain tumors, 29 and, in 5 patients, it was proven that this was caused by MLH1 or MSH2 germline mutations. 30,31 Another explanation may be that other selective advantages of MMR-deficient cells, such as resistance to apoptosis, played an important role in the development of our patient's brain tumor. 32 In Case IV, both the oligodendroglioma and the medulloblastoma in the patient's brother had low MSI.…”