Cutaneous and systemic plasmacytosis.
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Aged↗
Biomedical subjects
David Ramsey
Publications and source records attributed to David Ramsey.
Influence of polymorphisms in xenobiotic-metabolizing genes and DNA-repair genes on diepoxybutane-induced SCE frequency.
Analysis of the combined effects of polymorphisms in genes encoding xenobiotic metabolizing enzymes (XMEs) and DNA repair proteins may be a key to understanding the role of these genes in the susceptibility of individuals to mutagens. In the present study, we performed an in vitro experiment on lymphocytes from 118 healthy donors that measured the frequency of diepoxybutane (DEB) induced sister chromatid exchanges (SCEs) in relation to genetic polymorphisms in genes coding for XMEs (CYP1A1, CYP2E1, GSTT1, EPHX, and NAT2), as well as DNA repair proteins (XRCC1, XRCC2, XRCC3, XPD, XPA, XPC, XPG, XPF, ERCC1, BRCA1, NBS1, and RAD51). We found that GSTT1(-) and CYP2E1 c1/c2 polymorphisms were associated with higher DEB-induced SCE frequencies, and that NAT2 G(590)A was associated with lower SCE induction by DEB. Analysis of the effect of pairs of genes showed that for a fixed GSTT1 genotype, the SCE level increased with an increasing number of Tyr alleles in EPHX codon 113. We found that among GSTT1(+) individuals the DEB-induced SCE level was significantly lower when the EPHX 139 codon was His/Arg rather than His/His. An interaction between polymorphisms in CYP2E1 and at EPHX codon 113 was also observed. The results of our study confirm observations in cancer patients and in people exposed to xenobiotics indicating that sensitivity to mutagens depends upon a combined effect of a variety of "minor impact" genes. Moreover, our results indicate that polymorphisms in genes coding for XMEs have a greater influence on the genotoxic activity of DEB, measured by DEB-induced SCE frequency, than polymorphisms in genes encoding DNA repair proteins.
Adult↗
Three distinct regions of deletion on 13q in squamous cell carcinoma of the larynx.
Genetic etiology of squamous cell carcinoma of the larynx (SCCL) is very complex, with both molecular and chromosomal alterations involved. The target genes have not yet been clearly identified. Therefore, our study focused on searching for regions that potentially harbor genes related to SCCL. After comparative genomic hybridization (CGH) analysis of a set of 52 SCCL we specified 13q21-q32 and 13q34 as the most frequently deleted regions. In order to precisely map the critical region of deletion, we studied these areas by using 15 microsatellite markers. In our material a significantly high frequency of loss of heterozygosity (LOH) (test for a difference in two proportions, p<0.001) was observed for the following markers: D13S1320 (13q21.1), D13S800 (13q21.3), D13S1818 (13q32.1), D13S770 (13q32.3) and D13S285 (13q34). Three hot spots of LOH were found: 13q21.1-q22.1 (D13S1320-D13S1824-D13S800-SHGC30014- WI-16413-D13S1186), 13q.31.1-13q32.3 (D13S317-D13S1818-D13S770), 13q34 (D13S285). Among these areas, 13q31.1-q32.3 was identified as new hot spot of deletion in SCCLs.
Carcinoma, Squamous Cell↗
Significant involvement of chromosome 13q deletions in progression of larynx cancer, detected by comparative genomic hybridization.
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumours with various clinical characteristics. These tumours generally exhibit complex karyotypes. Few studies of genomic imbalances have been performed exclusively in subgroups of larynx cancer samples at different stages of the disease. In the present study, chromosomal gains and losses were investigated in 52 larynx tumours, by using comparative genomic hybridization (CGH). The mean number of observed alterations was 37.7 per tumour. The most common sites of losses were 1p, 13q, Xp, and the most common gains were located in 1p, 9q, 16q. The overall number of gains was negatively associated with cancer grading. G1 tumours were also characterized by a higher frequency of deletions in 13q32 and amplifications in 1q23, than tumours in other grades (p < 0.05). The frequency of losses of 13q22 also positively associated with tumour size. There was no association between the frequency of losses in 13q and the presence of lymph node metastases at the time of diagnosis. Another statistically significant association was observed for gains at 1q22-23 and tumour size (p < 0.01). No statistically significant difference in the frequency of most common imbalances was detected between primary tumours with lymph node metastases and those without metastases. In conclusion, we discovered a significant involvement of 13q deletions in the progression of larynx cancer. All the other significant changes observed in the present study were reported previously as being important for HNSCC progression. It seems that multiple genes are disrupted in the process of neoplastic transformation in the larynx, and the networks of events remain to be elucidated.
Carcinoma, Squamous Cell↗
Influence of GSTT1, mEH, CYP2E1 and RAD51 polymorphisms on diepoxybutane-induced SCE frequency in cultured human lymphocytes.
1,3-Butadiene (BD) is a common chemical in the human environment. Diepoxybutane (DEB) is the most reactive epoxide metabolite of BD. The aim of the present study was to evaluate the influence of polymorphisms in enzymes operating in DEB-metabolism (epoxide hydrolase mEH, CYP2E1 and GSTT1), as well as in the DNA-repair enzyme RAD51, on the frequency of sister chromatid exchange (SCE) induced by DEB in lymphocyte cultures from 63 healthy donors. Their genotypes were determined using PCR and restriction fragment length polymorphism (RFLP)-PCR techniques. The analysis of xenobiotic-metabolizing genes revealed that GSTT1 and CYP2E1 polymorphisms have an influence on DEB-induced SCE frequency. Individuals with the GSTT1 null genotype and CYP2E1 c2 variant allele heterozygotes were observed to have significantly higher SCE frequency than individuals with more common genotypes. A correlation between sensitivity to DEB and GSTT1 null genotype indicates that this pathway is a major detoxification step in DEB metabolism in whole-blood lymphocyte cultures, which has been shown in many studies. The analysis of combined polymorphisms indicated that, in the presence of GSTT1, a significantly higher DEB-induced SCE frequency is observed in the CYP2E1 c2 variant allele heterozygotes than in individuals with the most common CYP2E1 genotype. In the absence of GSTT1, however, the CYP2E1 polymorphism has no influence on DEB-induced SCEs. A significant difference was also observed between individuals characterized by low and high mEH activity, but only in subjects with the GSTT1 null genotype. Lack of GSTT1 resulted in higher SCE frequency in individuals with mEH high-activity genotypes than in individuals with mEH low-activity genotype. In the present study no statistically significant difference in DEB-induced SCEs was observed for the RAD51 polymorphism. The influence of GSTT1 genotype on SCE-frequency in RAD51 variant allele carriers was not analysed as all individuals in this group (except one person) had the GSTT1 gene present. Our study shows that the combined analysis of polymorphisms in metabolizing enzymes may lead to a better understanding of their contribution to an individual's susceptibility to DEB.
Base Sequence↗
Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene in squamous cell carcinoma of the larynx.
Defects in the system controlling the cell cycle can lead an increased proliferation of cancer cells. The aim of our study was to analyze the relationship between genetic changes leading to inactivation of the CDKN2A gene and subsequent alteration of protein expression in squamous cell cancer of the larynx (SCCL) in connection with the clinical and histopathological course of the disease. Analysis was carried out on DNA isolated from the blood and primary larynx cancer cells of 62 patients. To investigate loss of heterozygosity (LOH), PCR fragment analysis was applied. The size and quantity of fluorescent PCR products were evaluated in an automated sequencer. Specific chemical methylation with sodium bisulfite in a sequential PCR reaction (MSP) was applied to analyze promoter methylation. Cancer tissue sections served to determine the level of protein expression with immunohistochemical (IHC) staining and commercial antibodies. LOH at the CDKN2A locus was observed in 55.35% of the informative cases. Aberrant methylation was found in 37.5% and a decreased level of protein expression observed in 45% of all informative cases. Whenever P16 expression was decreased, LOH and promoter hypermethylation at CDKN2A were observed with a frequency of 73.33% and 80.95%, respectively (Fisher's test, P<0.005). Sixty-nine percent of G3 tumors had at least one genetic alteration at CDKN2A, compared with 40.9% of G1 cancers. The results indicate that CDKN2A inactivation played a significant role in the development of squamous cell carcinoma of the larynx.
Adult↗
Correlation among loss of heterozygosity, promoter methylation and protein expression of MLH1 in larynx cancer.
Extensive molecular studies in development of the squamous cell carcinoma of larynx (SCCL) indicated the involvement of a variety of genes including the MLH1. To search for possible mechanism leading to MLH1 silencing in SCCL we studied LOH and promoter methylation in a homogeneous set of 62 larynx cancers. Then we evaluated immunohistochemically the MLH1 expression for 51 tumor specimens. Further, the results were correlated with microsatellite instability and subsequently with the clinical course of the disease. LOH at the MLH1 locus and aberrant methylation of its promoter were found in 47.9 and in 22.6% of tumors, respectively. A decreased expression was observed in 27.5% of the cases. MSI analysis of tumor DNA showed a microsatellite stable phenotype in 59 cases (95.2%). From our study it can be concluded that: i) molecular alterations of MLH1 play an important role in SSCL development, ii) both LOH and aberrant methylation contribute to the MLH1 inactivation in SCCL and are associated with a less advanced stage of differentiation of larynx tumors, iii) MLH1 inactivation does not lead to MSI in larynx cancer and MSI may not contribute to the development of SCCL.
Adaptor Proteins, Signal Transducing↗
Cyclin D1 and MLH1 levels in laryngeal cancer are linked to chromosomal imbalance.
BACKGROUND: Carcinogenesis results from the accumulation of genetic alterations forming a functional network leading to genetic instability as a cardinal feature. Thus, the hypothesis that down-regulation of MLH1 in combination with aberrant cell cycle control may contribute to chromosomal instability in LSCC was tested. PATIENTS AND METHODS: Fifty-two patients, diagnosed with primary LSCC, none of whom had a history of hereditary cancer, were evaluated by comparative genomics. The expression of selected proteins controlling the cell cycle and mismatch repair was assessed with immunostaining. RESULTS: In our set, 1720 chromosomal imbalances were found, as well as altered protein synthesis including a decrease in RB1 and CDKN2A (10.2% and 44% of cases, respectively), an increase in CCND1 (47%) and a decrease in MLH1 (22.7%). Variation analysis correlating proteins, chromosomal imbalances and clinicohistopathological features of disease disclosed an association between chromosomal gains, low histopathological grade of tumour and CCND1 over-expression accompanied by a decrease in MLH1 expression (p < 0.01). CONCLUSION: CCND1 and MLH1 seem functionally interconnected in regard to chromosomal imbalances in larynx cancer.
Adaptor Proteins, Signal Transducing↗