Search

Purpose: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics.Experimental Design: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter.Results: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC.Conclusion: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.

Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-β) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-β treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-β-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 10-6) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10-5) and near ZNF697 (combined P-value 8.15 × 10-5). Refereed/Peer-reviewed

Schnyder crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease characterized by progressive corneal opacification resulting from abnormal deposition of cholesterol and phospholipids. Recently, six different mutations on the UBIAD1 gene on chromosome 1p36 were found to result in SCCD. The purpose of this article is to further characterize the mutation spectrum of SCCD and identify structural and functional consequences for UBIAD1 protein activity. DNA sequencing was performed on samples from 36 individuals from 14 SCCD families. One affected individual was African American and SCCD has not been previously reported in this ethnic group. We identified UBIAD1 mutations in all 14 families which had 30 affected and 6 unaffected individuals. Eight different UBIAD1 mutations, 5 novel (L121F, D118G, and S171P in exon 1, G186R and D236E in exon 2) were identified. In four families with DNA samples from both affected and unaffected individuals, the D118G, G186R, T175I, and G177R mutations cosegregated with SCCD. In combination with our previous report, we have identified the genetic mutation in UBIAD1 in 20 unrelated families with 10 (including 5 reported here), having the N102S mutation. The results suggest that N102S may be a mutation hot spot because the affected families were unrelated including Caucasian and Asian individuals. There was no genotype phenotype correlation except for the T175I mutation which demonstrated prominent diffuse corneal haze, typically without corneal crystals. Protein analysis revealed structural and functional implications of SCCD mutations which may affect UBIAD1 function, ligand binding and interaction with binding partners, like apo E.

Multiple sclerosis (MS) is one of the most common inflammatory and degenerative autoimmune diseases of the central nervous system with considerable heterogeneity in all aspects, including response to therapy. A number of disease modifying drugs, including traditional first line agents such as, interferon-beta (IFN-β) and glatiramer acetate (GA) are available for disease management. However, a considerable number of patients fail to achieve adequate response at therapeutic doses of IFN-β or GA. This variability in response to treatment has prompted the search for prognostic markers in order to personalize and optimize therapy so as to treat MS more efficiently. This review will summarize the existing literature examining the pharmacogenomics of IFN-β and GA response in MS patients. Refereed/Peer-reviewed

Purpose: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics. Experimental Design: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter. Results: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC. Conclusion: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.

PURPOSE. Schnyder crystalline corneal dystrophy (SCCD; MIM 121800) is a rare autosomal dominant disease characterized by an abnormal increase in cholesterol and phospholipid deposition in the cornea, leading to progressive corneal opacification. Although SCCD has been mapped to a genetic interval between markers D1S1160 and D1S1635, reclassification of a previously unaffected individual expanded the interval to D1S2667 and included nine additional genes. Three candidate genes that may be involved in lipid metabolism and/or are expressed in the cornea were analyzed. METHODS. DNA samples were obtained from six families with clinically confirmed SCCD. Analysis of FRAP1, ANGPTL7, and UBIAD1 was performed by PCR-based DNA sequencing, to examine protein-coding regions, RNA splice junctions, and 5 untranslated region (UTR) exons. RESULTS. No disease-causing mutations were found in the FRAP1 or ANGPTL7 gene. A mutation in UBIAD1 was identified in all six families: Five families had the same N102S mutation, and one family had a G177R mutation. Predictions of the protein structure indicated that a prenyl-transferase domain and several transmembrane helices are affected by these mutations. Each mutation cosegregated with the disease in four families with DNA samples from both affected and unaffected individuals. Mutations were not observed in 100 control DNA samples (200 chromosomes). CONCLUSIONS. Nonsynonymous mutations in the UBIAD1 gene were detected in six SCCD families, and a potential mutation hot spot was observed at amino acid N102. The mutations are expected to interfere with the function of the UBIAD1 protein, since they are located in highly conserved and structurally important domains. (Invest Ophthalmol Vis Sci. 2007;48: 5007‐5012) DOI:10.1167/iovs.07-0845

The authors regret that on page 182, in Section 3.7, ‘Candidate gene– (permutation p values p = 0.017 and p = 0.035, respectively) may gene interactions’ (last paragraph of the section) should read as follows. By applying the same statistical algorithmasO'Doherty and colleagues, Kulakova et al. found that patients carrying triallelic combinations of CCR5*d + IFNAR1*G + IFNB1*T/T and CCR5*d +IFNAR1*G + IFNG*T