Type A microsatellite instability in pediatric gliomas as an indicator of Turcot syndrome

Abstract

Microsatellite instability (MSI) is present in hereditary conditions due to mismatch repair (MMR) gene mutations. Following MSI analysis, tumor samples are classified into MSS (stable), MSI-L (low instability), and MSI-H (high instability) based on the fraction of unstable loci. Another MSI-based classification takes into account the size difference between mutant alleles in tumor DNA compared to wild-type alleles; two types of MSI, A and B, are recognized using this approach, type A being characterized by smaller, more subtle allelic shifts compared to type B. Biallelic mutations of MMR genes are associated with pediatric cancers, including glial tumors, in Turcot syndrome type 1 (TS1). However, most TS1-associated gliomas so far analyzed did not display MSI. We investigated the frequency of MSI in a series of 34 pediatric gliomas of different grade using a panel of five mononucleotide quasimonomorphic markers. Subtle qualitative changes were observed for the majority of markers in two glioblastomas (5.9% of the total series and 33.3% of glioblastomas). In both cases, family histories were compatible with TS1, and mutations of the PMS2 and MLH1 genes were identified. In one family, the MSI patterns were compared between the glioblastoma and a colon cancer from an affected relative, showing a clear qualitative difference, with the former displaying type A and the latter type B instability, respectively. These results were confirmed using additional microsatellite markers, indicating that knowledge of the association between TS1-related glial tumors and subtle type A MSI is important for full ascertainment of TS1 patients and appropriate counselling.

Constitutional mismatch repair-deficiency syndrome

“…MSI analysis follows current protocols used for LS-screening; however, this analysis may be unreliable in CMMR-D related brain tumors. 7,11,21 IHC is a useful technique employed in patients with CMMR-D associated neoplasms including brain tumors and guides subsequent mutation analysis in the four MMR-genes. In general, a truncating mutation in PMS2 or MSH6 will result in isolated loss of these proteins, whereas a mutation in MLH1 or MSH2 will lead to concurrent loss of MLH1/PMS2 or MSH2/MSH6, respectively, since MLH1 and MSH2 are the obligatory partners in the formation of MLH1/PMS2 and MSH2/MSH6 heterodimers.…”

Genetic Instability in Paediatric and Adult Brain Tumours

“…In contrast to colorectal cancer, which presents mainly Type B MSI, we and others have shown that high-grade gliomas harbour Type A MSI (Giunti et al, 2009;Viana-Pereira et al, 2009, 2011. 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).…”

“…When one or two markers present alterations tumours are classified as MSI-L; when all markers are normal tumours are classified as microsatellite stable (MSS) (Buhard et al, 2006;Umar et al, 2004;. In parallel with this classification, an alternative qualitative distinction of MSI, which considers the size of the allelic shifts in the markers, has been proposed (Giunti et al, 2009;Oda et al, 2005). Samples presenting small length changes (6 bp) are designed Type A MSI whereas those with more extreme variations are defined as Type B MSI.…”

Brain Tumors and the Lynch Syndrome

“…Since MSI is generally uncommon in brain tumors (see previous section), its presence may pinpoint MMR gene germline mutation carriers (Giunti et al, 2009). In a series of 34 pediatric gliomas of different grades, Giunti et al (2009) found two with MSI and both patients subsequently revealed germline mutations in MMR genes (biallelic in one and monoallelic in the other case) compatible with TS. Interestingly, a clear qualitative difference in the MSI pattern was evident when a glioblastoma from a TS patient and a colon cancer from an affected relative were compared.…”

“…Studies suggest that the presence of multiple subclones may be a general characteristic of MSI tumors from LS and sporadic settings (Fujiwara et al, 1998;Barnetson et al, 2000). Since MSI is generally uncommon in brain tumors (see previous section), its presence may pinpoint MMR gene germline mutation carriers (Giunti et al, 2009). In a series of 34 pediatric gliomas of different grades, Giunti et al (2009) found two with MSI and both patients subsequently revealed germline mutations in MMR genes (biallelic in one and monoallelic in the other case) compatible with TS.…”