Genetic analysis for early diagnosis of otorhinolaryngeal diseases

Familiarity with the concepts and methods of human genetics is important in order to be able to perform genetic analysis

Frequency of Microsatellite Instability in Unselected Sebaceous Gland Neoplasias and Hyperplasias

Sebaceous gland neoplasias are the cutaneous manifestation of the Muir–Torre syndrome, which is known to be a phenotypical variant of hereditary nonpolyposis colorectal cancer. Both hereditary nonpolyposis colorectal cancer and Muir–Torre syndrome are caused by inherited DNA mismatch repair defects. As a prominent molecular genetic feature, all tumors associated with a DNA mismatch repair defect exhibit high microsatellite instability. So far, the frequency of DNA mismatch repair defects in patients selected solely on the basis of a sebaceous gland tumor has never been determined. In order to estimate this frequency, we assessed microsatellite instability with up to 10 microsatellite markers in a newly collected unselected series of 25 sebaceous gland neoplasias (six sebaceous adenomas, 16 sebaceous epitheliomas, three sebaceous carcinomas) in comparison to 32 sebaceous gland hyperplasias from unrelated patients. As many as 15 of the 25 sebaceous gland neoplasias (60%), but only one of the 32 sebaceous gland hyperplasias (3%), exhibited high microsatellite instability. Thus, in our study, the majority of patients with a sebaceous gland neoplasia in contrast to patients with a sebaceous gland hyperplasia are highly suspicious for an inherited DNA mismatch repair defect. On the basis of the subsequently collected tumor histories, nine of the 15 patients with a high microsatellite unstable sebaceous gland neoplasia were identified to have Muir–Torre syndrome. In none of these cases, however, were the clinical Amsterdam criteria for diagnosing hereditary nonpolyposis colorectal cancer fulfilled. In the sebaceous tumors of the remaining six patients, high microsatellite instability was an incidental finding. In two of these six patients, single relatives were known to be affected with internal cancer; however, their family histories were not suggestive of Muir–Torre syndrome or hereditary nonpolyposis colorectal cancer. In comparison with microsatellite instability screening studies in a variety of other randomly selected tumors, our study identifies sebaceous gland neoplasias as tumors with the highest frequency of high microsatellite instability reported so far, whereas sebaceous gland hyperplasia rarely exhibits high microsatellite instability. Therefore, screening for microsatellite instability in sebaceous gland neoplasias will be of great value in the detection of an inherited DNA mismatch repair defect, which predisposes to various types of internal cancers

Association between TAS2R38 gene polymorphisms and colorectal cancer risk

Molecular sensing in the lingual mucosa and in the gastro-intestinal tract play a role in the detection of ingested harmful drugs and toxins. Therefore, genetic polymorphisms affecting the capability of initiating these responses may be critical for the subsequent efficiency of avoiding and/or eliminating possible threats to the organism. By using a tagging approach in the region of Taste Receptor 2R38 (TAS2R38) gene, we investigated all the common genetic variation of this gene region in relation to colorectal cancer risk with a case-control study in a German population (709 controls and 602 cases) and in a Czech population (623 controls and 601 cases). We found that there were no significant associations between individual SNPs of the TAS2R38 gene and colorectal cancer in the Czech or in the German population, nor in the joint analysis. However, when we analyzed the diplotypes and the phenotypes we found that the non-taster group had an increased risk of colorectal cancer in comparison to the taster group. This association was borderline significant in the Czech population, (OR = 1.28, 95% CI 0.99-1.67; P(value) = 0.058) and statistically significant in the German population (OR = 1.36, 95% CI 1.06-1.75; P(value) = 0.016) and in the joint analysis (OR = 1.34, 95% CI 1.12-1.61; P(value) = 0.001). In conclusion, we found a suggestive association between the human bitter tasting phenotype and the risk of CRC in two different populations of Caucasian origin

A Gene for Universal Congenital Alopecia Maps to Chromosome 8p21-22

SummaryComplete or partial congenital absence of hair (congenital alopecia) may occur either in isolation or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal-recessive mode of inheritance (MIM 203655). As yet, no gene has been linked to isolated congenital alopecia, nor has linkage been established to a specific region of the genome. In an attempt to map the gene for the autosomal recessive form of the disorder, we have performed genetic linkage analysis on a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia). We have analyzed individuals of this family, using >175 microsatellite polymorphic markers of the human genome. A maximum LOD score of 7.90 at a recombination fraction of 0 has been obtained with locus D8S258. Haplotype analysis of recombination events localized the disease to a 15-cM region between marker loci D8S261 and D8S1771. We have thus mapped the gene for this hereditary form of isolated congenital alopecia to a locus on chromosome 8p21-22 (ALUNC [alopecia universalis congenitalis]). This will aid future identification of the responsible gene, which will be extremely useful for the understanding of the biochemistry of hair development

On the problem of supersonic gas flow in two-dimensional channel with the oscillating upper wall

In the present paper we solve the problem of supersonic gas flow in two-dimensional channel with the moving upper wall making oscillations according to the harmonic law. In order to get a numerical solution for gas dynamics equations we have implemented a difference scheme with space and time approximation of the first order and one with space approximation of the second order. Depending on a type of harmonic law and initial gas inflow conditions, the peculiarities of angle-shock wave propagation in moving curvilinear domains have been investigated. It has been determined that the increase of oscillation amplitude causes the increase of shock wave intensity. It has been shown that under particular oscillation amplitude the moving wall has practically no effect on the flow within the domain

Polymorphisms of genes coding for ghrelin and its receptor in relation to colorectal cancer risk: a two-step gene-wide case-control study

<p>Abstract</p> <p>Background</p> <p>Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also indicates a role of ghrelin in cancer development.</p> <p>Methods</p> <p>We conducted a case-control study to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with colorectal cancer risk. Pairwise tagging was used to select the 11 polymorphisms included in the study. The selected polymorphisms were genotyped in 680 cases and 593 controls from the Czech Republic.</p> <p>Results</p> <p>We found two SNPs associated with lower risk of colorectal cancer, namely SNPs rs27647 and rs35683. We replicated the two hits, in additional 569 cases and 726 controls from Germany.</p> <p>Conclusion</p> <p>A joint analysis of the two populations indicated that the T allele of rs27647 SNP exerted a protective borderline effect (P_trend= 0.004).</p

Recurrent Coding Sequence Variation Explains only A Small Fraction of the Genetic Architecture of Colorectal Cancer

Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10-7), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10-7); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10-

Monoamine related functional gene variants and relationships to monoamine metabolite concentrations in CSF of healthy volunteers

BACKGROUND: Concentrations of monoamine metabolites in human cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. CSF monoamine metabolite concentrations are partly determined by genetic influences. METHODS: We investigated possible relationships between DNA polymorphisms in the serotonin 2C receptor (HTR2C), the serotonin 3A receptor (HTR3A), the dopamine D(4 )receptor (DRD4), and the dopamine β-hydroxylase (DBH) genes and CSF concentrations of 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 90). RESULTS: The HTR3A 178 C/T variant was associated with 5-HIAA levels (p = 0.02). The DBH-1021 heterozygote genotype was associated with 5-HIAA (p = 0.0005) and HVA (p = 0.009) concentrations. Neither the HTR2C Cys23Ser variant, nor the DRD4 -521 C/T variant were significantly associated with any of the monoamine metabolites. CONCLUSIONS: The present results suggest that the HTR3A and DBH genes may participate in the regulation of dopamine and serotonin turnover rates in the central nervous system

Association Between TAS2R38 Gene Polymorphisms and Colorectal Cancer Risk: A Case-Control Study in Two Independent Populations of Caucasian Origin

Molecular sensing in the lingual mucosa and in the gastro-intestinal tract play a role in the detection of ingested harmful drugs and toxins. Therefore, genetic polymorphisms affecting the capability of initiating these responses may be critical for the subsequent efficiency of avoiding and/or eliminating possible threats to the organism. By using a tagging approach in the region of Taste Receptor 2R38 (TAS2R38) gene, we investigated all the common genetic variation of this gene region in relation to colorectal cancer risk with a case-control study in a German population (709 controls and 602 cases) and in a Czech population (623 controls and 601 cases). We found that there were no significant associations between individual SNPs of the TAS2R38 gene and colorectal cancer in the Czech or in the German population, nor in the joint analysis. However, when we analyzed the diplotypes and the phenotypes we found that the non-taster group had an increased risk of colorectal cancer in comparison to the taster group. This association was borderline significant in the Czech population, (OR = 1.28, 95% CI 0.99–1.67; Pvalue = 0.058) and statistically significant in the German population (OR = 1.36, 95% CI 1.06–1.75; Pvalue = 0.016) and in the joint analysis (OR = 1.34, 95% CI 1.12–1.61; Pvalue = 0.001). In conclusion, we found a suggestive association between the human bitter tasting phenotype and the risk of CRC in two different populations of Caucasian origin