Role of Genetic Polymorphisms in Metastasis Suppressor Genes NME1 and MKK4 as Breast Cancer metastasis modifiers.

Breast cancer in women is a major health burden both in developed and developing countries and is the second leading cause of death in women worldwide. Although, the risk of developing breast cancer is modified by environment, lifestyle, genetics and a combination of these factors, the principal factor contributing to cancer-related deaths in cancer patients is metastasis. A class of genes, known as metastasis suppressor genes which play an important role in metastasis have been identified. Malfunction of these genes due to somatic mutation or epigenetic modulations, can influence metastatic dissemination. Genetic polymorphisms in metastatic suppressor genes like NME1 and MKK4 are not well studied in breast cancer. Given the importance of metastasis in the prognosis of breast cancer it makes sense to study such genotypes and their possible association with aggressiveness as well as prognosis of the cancer. Hence we analyzed the relationship between NME1 and MKK4 polymorphisms and breast cancer risk in Kashmir, India.Digital copy of Thesis.University of Kashmir

Association of a Chromosomal Susceptibility Locus to Bipolar Affective Disorder (BPAD): A case-control study in Kashmir

The etiology of bipolar disorder (BPAD) is still unknown, but family, twin, and adoption studies strongly suggest the involvement of genetic risk factors. Linkage studies have revealed a number of loci to be linked with BPAD. Of those, several investigators confirmed 18p11 as one of the susceptibility loci for BPAD. Thus, chromosome 18p11 is one of the targets of the genetic association study of BPAD. The aim of our study was to investigate whether the tandem repeat polymorphism in D18S452 microsatellite marker at locus 18p11.2 is a risk factor for the development of BPAD in Kashmiri population. The repeat polymorphism in D18S452 was evaluated in 74 patients with BPAD and 74 control (age, sex and region matched) individuals. The repeat polymorphism was evaluated by PCR analysis of DNA obtained from the blood of the subjects. We observed that the tandem repeat (300bp*) allele frequency was found to be 1.35 % in the controls and 8.108% in cases. The tandem repeat (250bp*) allele frequency was found to be in 91.89% in cases and 98.65% in controls. The 252bp/252bp genotype was found to be present in 89.18% of the cases and 98.64% of the controls, the 300bp/300bp genotype in 5.40% of cases and 1.35% of controls and the 252bp/300bp variant in 5.40% of the cases and none among the controls. It was observed that although the proportion of patients homozygous for the tandem repeat (300bp/300bp) was higher in cases than in controls, the difference was not statistically significant when using 252bp/252bp genotype as a reference (OR= 4.4242; 95% CI, 0.4822-40.5924); P = 0.1529). However, it was observed that the frequency of the heterozygous genotype (252bp/300bp) when compared with 252bp/252bp showed statistical significance (OR=8.0603; 95% CI, 1.1112-58.4646; P = 0.0383). Chromosome 18 harbors many candidate genes that are involved in the pathophysiology of BPAD. It may be possible that this marker is directly or indirectly involved in the regulation of neighboring genes. It is also possible that this locus may be in linkage disequilibrium with other genes. Although, this is the first study reporting the association of the marker D18S452 in heterozygous condition (252bp/300bp) with BPAD. Yet, it would be too early to associate this genotype with the predisposition to BPAD. Therefore, further studies with larger sample size should be carried to validate the result, taking into account the various disease phenotypes, endophenotypes and environmental conditions

Comparison of Alcohol Dehydrogenase 2 and Aldehyde Dehyrdogenase 2 Polymorphism in Esophageal Cancer Cases vs Controls in Kashmir

The esophageal cancer (EC) is the most common cancer in Kashmir and its causes are not yet clearly understood. The current study was designed with the aim of understanding the association of known genotypes in ADH2 and ALDH2 genes and role of local dietary habits like consumption of salt tea, socioeconomic status and smoking with esophageal cancer risk. We analyzed 50 histopathologically confirmed esophageal cancer cases and same number of age, sex, and region matched nonmalignant controls. The data on dietary history/tobacco consumption/family history of cancer/fruit consumption and economic status was collected through a well drafted questionnaire. Male and female ratio among 50 esophageal cancer patients registered came out to be 1:1.63 which is contrary to the previously reported 1:2. Highest number of esophageal cases turned out from southern region of Kashmir. The low fruit consumption (86.0%), low socio-economic status (70.00%) and very frequent consumption of salt tea (98%) were the common features in our cases which can be strong risk factors for EC in valley. The family history of the subjects turned out to be another potential risk factor for EC in Kashmir as about 22.00% of cases have family history of cancer. Most of the cases (74.00%) were smokers which is an established risk factor for EC. The genetic analysis of the cases and controls by PCR-CTPP method, for the genotypic frequencies in ADH2 and ALDH2 genes revealed that unlike other high risk regions, Kashmiri population has a different standing. ADH2 allele that encodes ADH enzyme with high activity or ALDH2 allele that encodes ALDH enzyme with particularly low activity lead to the accumulation of acetaldehyde and increase the risk of developing esophageal cancer. In the present cohort of cases, SNPs in ADH2 and ALDH2 do not confer any risk of esophageal cancer development in Kashmir. The frequency of ADH2*2 and ALDH2*2 mutant alleles was found to be 39.5% and 5% respectively. The results when compared with the mutant allele frequencies of the other high risk regions of EC support the fact that the mutant alleles of the two genes are highly frequent in East Asia only and in the rest of the world their frequencies are low

اردو ذبان وادب کی ترقی میں مستشرقین کا حصہ (Urdu Zaban-o-Adab ki taraqi mein mustashriqeen ka hissa.)

NADigital copy of Thesis.University of Kashmir