Esophageal cancer is one of the most lethal cancers highly prevalent in India. Esophageal squamous cell carcinoma (ESCC), the predominant form of esophageal cancer in the country, is an aggressive cancer associated with high mortality. Due to the relatively late stage of diagnosis and ineffective treatment options; the five-year survival rate may be as low as 10%, especially when diagnosed at stage III and IV. Surgery is the most common form of treatment, however it usually offers very low chance of recovery. Moreover, recurrent metastatic tumours are often refractory to currently available chemotherapeutic options. Like any other cancer, ESCC is also thought to arise from a series of genetic changes; therefore it is important to identify and characterize these genetic events. The recent advent of microarray technology has resulted in rapid advances in our knowledge of the biology of cancers particularly those occurring in breast, prostate, lung, skin, blood and colon. However, little work has been carried out to improve our understanding of the molecular events leading to the initiation and progression of ESCC. Recurrent DNA amplifications and deletions occurring at specific chromosomal locations reveal genes involved in tumour progression. Earlier studies using Comparative Genomic Hybridization (CGH) have identified a few regions of deletions and amplifications associated with ESCC, however due to the inherent low resolution associated with conventional CGH, it is usually difficult to identify critical genes within the amplifications and deletions. However, the advent of array-based CGH (aCGH) has alleviated this lacuna. We propose to utilize a combination of aCGH and gene expression microarrays to identify localized high level DNA amplifications and homozygous deletions. This will enable us to determine novel genes that may play a crucial role in the initiation and progression of ESCC; the gene products can be tested in follow-up studies for the identification of novel drug targets.


3. Molecular genetic analyses of Familial Hypertrophic Cardiomyopathy in Andhra Pradesh;, a project carried out in collaboration with Care Hospital, Hyderabad and Usha Mullapudi Hospital, Hyderabad.

Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disease with variable clinical and morphologic expression and is the most common cause of sudden death in otherwise healthy individuals. The two prominent clinical features are left ventricular hypertrophy and myocyte/myofibrillar disarray. The clinical heterogeneity has been linked to genetic heterogeneity; mutations in at least eleven genes encoding sarcomere proteins have been shown to be the molecular basis for the disorder. Additional genetic loci, as well as nongenetic factors such as lifestyle, sex, and age, have also been shown to play a role in modulating the clinical presentation of the disease. Our studies on an Indian family have revealed a mutation (p.R870H) in the MYH7 gene. More importantly we have shown that Gender may be a stronger modulator of clinical presentation of disease as compared to the ace gene polymorphism for patients with this mutation. Studies being carried out should 1) reveal mutations prevalent in the population, 2) help in establishing genotype-phenotype correlations and 3) provide management to affected families through genetic counseling.

4. Molecular studies on genetic disorders in Andhra Pradesh, in collaboration with Diagnostics Division, CDFD.

The Diagnostics Division carries out testing for several biochemical, chromosomal and genetic disorders. In a joint effort, we have initiated molecular genetic screening for several genetic disorders. These presently include beta-thalassemia (for rare mutations), Farbers disease and Phenylketonuria. Our work has revealed the complete mutation profile in beta-thalassemia patients in Andhra Pradesh, when compared to rest of the country. We have also detected rare mutations in the Anthra Pradesh that have not been reported from India so far. With no effective prevention available for beta-thalassemia, carrier detection and prenatal diagnosis are the most feasible mode of prophylaxis available and our efforts are an important step to complete the catalogue of mutations from the South Indian population. We have also initiated work on screening for mutations for Phenylketonuria and Farbers disease. Our results have revealed the existence of novel disease causing mutations for Farber disease and Phenylketonuria that have not been reported elsewhere in the world.