Vitamin D receptor gene variations and their haplotypic association: Possible impact on gastric cancer risk.

Background: Vitamin D receptor (VDR) gene alterations have been associated with the occurrence and prognosis of various types of cancers, but only few studies have focussed on gastric cancer (GC) risk. Objectives: This case-control study was conceived to evaluate possible association of VDR polymorphisms (Fok1, Taq1, and Cdx2) with GC risk. Materials and Methods: A total of 293 subjects, including 143 GC patients and 150 controls were included in this study. The genotypes were elucidated by polymerase chain reaction-restriction fragment length polymorphism followed by DNA sequencing. Results: The frequency of Fok1 genotypes (TC and TT) was found higher in GC cases compared to controls (P ≤ 0.05). In the stratified analysis, we observed a significant association of the (CT + TT) variant with GC risk in males, rural dwellers, smokers, and preobese cases, and those having no family history of Gastrointestinal cancer (P ≤ 0.05). In silico analysis predicted that the Fok1 variant impacts the stability and functional efficiency of the protein. Some exact haplotypes (CCG and CCA) of the VDR gene may act as low penetrance alleles in inclination to GC. Conclusion: VDR Fok1 polymorphism is significantly associated with GC risk in the Kashmiri population. Specific haplotypes in the VDR gene could act synergistically in the development of GC.

Evaluation of chromosome 1p/19q deletion by Fluorescence in Situ Hybridization (FISH) as prognostic factors in malignant glioma patients on treatment with alkylating chemotherapy.

BACKGROUND: Either deletion or co-deletion of chromosomal arms 1p or 19q is a characteristic and early genetic event in oligodendroglial tumors that is associated with a better prognosis and enhanced response to therapy. Information of 1p/19q status is now regarded as the standard of care when managing oligodendroglial tumors for therapeutic options in anticipation of the increased survival and progression-free survival times associated with it. Keeping this in view, we first time attempted to establish the FISH based detection of 1p/19q deletion in glioma tissue samples to evaluate its role and involvement in the disease. METHOD: Overall 39 glioma cases of different histologies were evaluated by fluorescence in situ hybridization (FISH) technique using specific FISH probes with Olympus BX43 fluorescent microscope to detect chromosomes 1p and 19q or co-deletions therein. RESULTS: Of the 39 glioma samples, overall 27 (69.2%) were found to have deletion either in 1p, 19q or both. Deletions were observed in 23.0%, 7.6% and 38.4% in 1p, 19q and 1p/19q co-deletions respectively. Overall oligidendrioglioma presented with 53.8% (21 of 39) deletions, astrocytoma group showed 12.8% and GBM accounted for 2.5% deletions. Overall survival and disease free survival was seen significantly better in oligidendrioglioma and astrocytoma with deleted tumors as compared to non-deleted ones (p<0.05). CONCLUSION: Allelic losses on 1p and 19q, either discretely or shared, were more frequent in classic oligodendrogliomas than in either astrocytoma or Glioblastoma with better survival and response to therapy.

Concordant association validates MGMT methylation and protein expression as favorable prognostic factors in glioma patients on alkylating chemotherapy (Temozolomide).

O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and its subsequent loss of protein expression has been identified to have a variable impact on clinical outcome of glioma patients indicated for chemotherapy with alkylating agents (Temozolomide). This study investigated methylation status of MGMT gene along with in situ protein expression in malignant glioma patients of different histological types to evaluate the associated clinical outcome vis-a-vis use of alkylating drugs and radiotherapy. Sixty three cases of glioma were evaluated for MGMT promoter methylation by methylation-specific PCR (MS-PCR) and protein expression by immunostaining (IHC). Methylation status of MGMT and loss of protein expression showed a very high concordant association with better survival and progression free survival (PFS) (p < 0.0001). Multivariate Cox regression analysis showed both MGMT methylation and loss of protein as significant independent prognostic factors in glioma patients with respect to lower Hazard Ratio (HR) for better OS and PFS) [p < 0.05]. Interestingly concordant MGMT methylation and lack of protein showed better response in TMZ therapy treated patient subgroups with HR of 2.02 and 0.76 (p < 0.05). We found the merits of prognostication of MGMT parameters, methylation as well as loss of its protein as predictive factors for favorable outcome in terms of better survival for TMZ therapy.

Upregulation of vascular endothelial growth factor (VEGF), its role in progression and prognosis of non-small cell lung carcinoma.

Elevated VEGF mRNA (-ΔCT) was significantly associated with adenocarcinoma histology (vs squamous) and advanced NSCLC clinical stages in a univariable analysis; however, this association did not remain significant in the multivariable analysis. Of interest, a Kaplan-Meier analysis showed that NSCLC patients with higher VEGF mRNA (-ΔCT ≥10) had a significantly poorer overall survival and shorter postoperative relapse time in adenocarcinoma and in stage III/IV than those with VEGF mRNA of -ΔCT <10 (P < 0.001). The multivariable analysis confirmed that patients with higher VEGF mRNA levels, as well as with adenocarcinoma and advanced stages, were independent predictors of a poorer survival. However, only the histology of adenocarcinoma remained a significant prognostic factor of a shorter postoperative relapse in the multivariable model. Quantity of VEGF mRNA can be used as a prognosis factor to predict shorter overall survival in patients with NSCLC.

SNP and Haplotype Analysis of Vascular Endothelial Growth Factor (VEGF) Gene in Lung Cancer Patients of Kashmir

Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis involving tumor growth and metastasis. In this large case-control study, we investigated whether functional polymorphisms (+405C>G, +936C>T) in the VEGF gene are associated with the risk of lung cancer. The study investigates the association between variants of VEGF gene and lung cancer. We performed single nucleotide polymorphism (SNP), haplotype and linkage disequilibrium studies on 100 patients and 128 healthy controls with 2 SNPs in the VEGF gene. The results were analyzed using logistic regression models, adjusted for age and sex. No Significant association was detected between individual SNPs and lung cancer using all the models of inheritance (codominant, dominant, recessive, over dominant and additive) for finding an association between genotypes and the cancer risk. The P values obtained for two markers were nonsignificant (P>0.05). Haplotype analysis produced additional support for the non-association of individual haplotypes/ all haplotypes with the cancer risk (Global association P=0.56). Our findings suggest the non-involvement of genetic variants (+405C>G, +936C>T) of the VEGF gene in the etiology of lung cancer.

Contribution of TGFß1 codon 10 polymorphism to high myopia in an ethnic Kashmiri population from India.

This study looks at novel variants of the TGFß1 gene and their potential association with high myopia in an ethnic population from Kashmir, India. Allele frequencies of 247 Kashmiri subjects (from India) with high myopia and 176 ethnically matched healthy controls were tested for Hardy-Weinberg disequilibrium. The genotype and allele frequencies were evaluated using chi-square or Fisher's exact tests. One of the three SNPs in codon 10 showed a significant difference between patients and control subjects (rs1982073: p genotype = 0.003, p allele = 0.001). There were no statistically significant differences between patients and control subjects for the other two SNPs, rs1800471 at codon 25 and a novel variant at codon 52. SNP rs1982073, substituting proline with leucine, appeared to be significantly associated with high myopia (p < 0.05). In silico predictions show that substitutions are likely to have an impact on the structure and functional properties of the protein, making it imperative to understand their functional consequences in relation to high myopia.