Genomic alterations in low-grade, anaplastic astrocytomas and glioblastomas.

To extend our understanding of potential stepwise genetic alterations that may underlie tumor progression from low-grade astrocytomas to glioblastomas, histopathologic and comparative genomic hybridization analyses were performed on tumor specimens from 68 primary lesions, including 40 glioblastomas, 10 anaplastic and 18 low-grade astrocytomas. The number of aberrations per case increased towards the higher grade tumors (grade II: 1.66+/-1.49; grade III: 2.80+/-1.68; grade IV: 3.02+/-1.07; F=6.955, p=0.002). A gain of 7/7q was common and the most frequently seen aberration in low-grade astrocytomas, whereas loss of 10q was the most frequently seen anomaly in anaplastic astrocytomas and glioblastomas. Chromosome 7p amplification was only detected in glioblastomas. Chromosome 10/10q deletion and combination of 1p, 19q and 17p deletions were specific to high-grade astrocytic tumors. Sequences of chromosome 7 and 10 seem to have pivotal roles in the biology of human gliomas. The genomic copy deletions of chromosomes 1p and 19q might provide an alternative mechanism in the genesis of astrocytomas.

Relation of glutathione S-transferase genotypes (GSTM1 and GSTT1) to laryngeal squamous cell carcinoma risk.

The purpose of the present study was to investigate GSTM1 and GSTT1 genotypes by using multiplex polymerase chain reaction (PCR) in patients with laryngeal squamous cell carcinoma (LSCC). The genotypes of 110 patients with LSCC and of 197 healthy subjects as the control group were determined by PCR analysis for GSTM1 and GSTT1 genes. Results showed that frequencies of GSTM1-null, GSTT1-null, and both GSTs-null genotypes were 51.8, 30, and 16.4%, respectively, in the patients with LSCC and 37.6, 15.7, and 5.6% in the control group. There was a significant difference between the genotype distributions of all GSTs in patients and in control groups (P < 0.05). The results support the hypothesis that null genotypes of GSTM1 and GSTT1 can reduce detoxification capacity of GSTs as members of the xenobiotic enzyme system. GSTM1-null, GSTT1-null, and both GSTs-null genotypes were more common in the patients with LSCC than in the control group. Patients with both GSTs-null genotypes had the highest risk for supraglottic LSCC in the early period, even if they were light-to-medium smokers. Investigation and determination of the genetic basis of LSCC may contribute to detection of risk groups and to prevent LSCC in the population.

Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome.

Membrane cofactor protein (MCP; CD46) is a widely expressed transmembrane complement regulator. Like factor H it inhibits complement activation by regulating C3b deposition on targets. Factor H mutations occur in 10-20% of patients with hemolytic uremic syndrome (HUS). We hypothesized that MCP mutations could predispose to HUS, and we sequenced MCP coding exons in affected individuals from 30 families. MCP mutations were detected in affected individuals of three families: a deletion of two amino acids (D237/S238) in family 1 (heterozygous) and a substitution, S206P, in families 2 (heterozygous) and 3 (homozygous). We evaluated protein expression and function in peripheral blood mononuclear cells from these individuals. An individual with the D237/S238 deletion had reduced MCP levels and approximately 50% C3b binding compared with normal controls. Individuals with the S206P change expressed normal quantities of protein, but demonstrated approximately 50% reduction in C3b binding in heterozygotes and complete lack of C3b binding in homozygotes. MCP expression and function was evaluated in transfectants reproducing these mutations. The deletion mutant was retained intracellularly. S206P protein was expressed on the cell surface but had a reduced ability to prevent complement activation, consistent with its reduced C3b binding and cofactor activity. This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies.