Glioma Susceptibility 5

Watchlist
Retrieved
2019-09-22
Source
Trials
Genes
Drugs

For a general phenotypic description and a discussion of genetic heterogeneity of glioma, see GLM1 (137800).

Mapping

Working from the hypothesis that coinheritance of low-risk variants contributes to the 2-fold increased risk of glioma in relatives of individuals with primary brain tumors, Shete et al. (2009) conducted a metaanalysis of 2 glioma genomewide association studies by genotyping 550,000 tagged SNPs in a total of 1,878 cases and 3,670 controls, with validation in 3 additional independent series totaling 2,545 cases and 2,953 controls. They observed significant association of a single-nucleotide polymorphism (SNP), rs4977756 (OR = 1.24, 95% CI 1.19-1.30, P = 7.24 x 10(-15)) located 59 kb telomeric to the CDKN2B gene (600431) within a 122-kb region of linkage disequilibrium on chromosome 9p21.3. This region encompasses the CDKN2A (600160)-CDKN2B tumor suppressor genes, which have an established role in glioma. Homozygous deletion in CDKN2A is detectable in approximately 50% of tumors (Cancer Genome Atlas Research Network, 2008, Parsons et al., 2008), and loss of expression is linked to poor prognosis. Furthermore, germline mutation of CDKN2A causes the melanoma-astrocytoma syndrome (155755). Regulation of p16/p14(ARF) is important for sensitivity to ionizing radiation, the only environmental factor strongly linked to gliomagenesis.

Wrensch et al. (2009) conducted a principal component-adjusted genomewide association study of 275,895 autosomal variants among 692 adult high-grade glioma cases, 622 from the San Francisco Adult Glioma Study and 70 from the Cancer Genome Atlas, and 3,992 controls. The replication sample was performed in the 13 SNPs with a P value of less than 10(-6) using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic. On chromosome 9p21, rs1412829 near CDKN2B had a combined P value of 1.85 x 10(-10).

Molecular Genetics

Somatic Mutation

Bigner et al. (1988) found chromosome abnormalities in 12 of 54 malignant gliomas. Structural abnormalities of 9p were increased to a statistically significant degree. Olopade et al. (1992) found molecular evidence of deletion in 9p in 10 of 15 glioma-derived cell lines and 13 of 35 primary gliomas. The shortest region of overlap of these deletions mapped to the interval between the centromeric end of the interferon gene cluster and the methylthioadenosine phosphorylase locus (156540).

Simons et al. (1999) used representational difference analysis (RDA) of a human glioblastoma xenograft to isolate 5 tumor-associated homozygously deleted DNA fragments, all originating from the 9p21 region. Subsequent analysis of a series of 10 glioblastomas using the newly isolated RDA fragments in conjunction with a series of known 9p21 DNA markers revealed homozygous deletions in 9 of the 10 tumors. These deletions encompassed the p15 (CDKN2B) and p14/p16 (CDKN2A) complex and 2 additional putative tumor suppressor loci. The RDA fragments corresponded to the latter 2 loci. Taken together, these results suggested the involvement of multiple tumor suppressor genes from the 9p21 region in glioblastoma tumorigenesis.