| The identification and characterization of tumor suppressor genes leads to a better understanding not only of the malignancies in which they function abnormally, but also of the normal functioning of the cell. Meningioma is among the most frequently occurring brain tumors. Though usually benign, a subset are either refractory to surgical removal or malignant, and a much greater number recur despite surgical intervention. Evidence for a role of the short arm of human chromosome 1 (1p) has accumulated to suggest that the region might harbor a tumor suppressor gene important in meningioma as well as other tumors with characteristic deletions of 1p. A panel of 157 tumors was examined by loss of heterozygosity for deletions of 1p using a group of highly polymorphic markers and a 1.5 centimorgan smallest region of overlapping deletion (SRO) was identified. Deletion of 1p was predictive for tumor recurrence and correlated to deletion of chromosome 22 and inactivation of the NF2 tumor suppressor gene, molecular hallmarks in these tumors. An integrative mapping approach was used, CompView, which combined multiple genomic datasets. Markers identified in CompView were used to screen the emerging physical mapping and sequence databases of the genome. New polymorphic markers permitted narrowing of the SRO to a region ultimately defined by the microsatellite markers D1S421, distally, to D1S2134, proximally. A fully sequenced contig of the SRO was assembled spanning 2.8 megabases on 1p34. Expression profiling of the 59 genes in the region using custom-made, glass-slide cDNA microarrays identified 25 genes in the SRO whose differential expression was significantly associated with 1p LOH. Cross-referencing this group to a list of 17 genes identified by analysis of tumor suppressor gene ontologies yielded seven highly probable candidate suppressor genes: PTCH2, MKNK1, MAST205, TSPAN-1, SIL, PRDX1, and DD96. One of the genes, PTCH2, is a member of a Patched gene family, whose founding human member, PTCH, is responsible for the cancer predisposition syndrome, Gorlin or Basal Cell Nevoid Syndrome. Mutational analysis of PTCH2 in 23 tumors failed to identify tumor-specific mutations. Expression analysis showed no correlation to 1p LOH, making the gene an unlikely player in meningioma tumorigenesis. |
