Frequent loss of heterozygosity encompassing the hMLH1 locus in low grade astrocytic tumors

Abstract

The mismatch repair genes, hMLH1 (3p22) and hMSH2 (2p21), are commonly associated with accumulation of mutations and microsatellite instability. However, the status of their gene loci itself is often not addressed. In astrocytic tumors, the heterozygosity status of these genes with reference to tumor grade has not yet been determined. We have analyzed the heterozygosity status and locus specific instability in 43 glial tumors comprising 22 low grades diffuses astrocytoma (WHO Grade II, DA) and 21 glioblastoma multiforme (Grade IV GBM) using 10 microsatellite markers at 2p and 3p to elucidate the involvement of these loci in astrocytic tumorigenesis. We observed a significantly higher loss of heterozygosity (LOH) in 3p markers encompassing the hMLH1 gene locus in DA when compared to GBM (P=0.008). In DA, while the frequency of LOH was observed to be higher in markers close to the hMLH1 gene (∼40%), locus specific microsatellite instability (LSI) was higher (∼30%) in markers localizing further to the gene. The frequency of LOH at markers on 2p, near the hMSH2 gene was, however, similar in DA and GBM (P=0.451). Our results suggest that in the astrocytic tumorigenesis, LOH at the hMLH1 gene locus is an early event in tumorigenesis. However, the mismatch repair protein expression may be regulated by other cellular factors.