Esophageal squamous cell carcinoma (ESCC), the predominant form of esophageal cancer in the country, is an aggressive cancer associated with high mortality. Adenocarcinoma of the esophagous is more common in the western countries. Due to the relatively late stage of diagnosis and ineffective treatment options; the five-year survival rate in ESCC may be as low as 10%. Recurrent metastatic tumours are often refractory to currently available herapeutic regimes. 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. Array-based CGH (aCGH) has made it possible to identify copy number alterations at a high resolution. We have commenced the study to determine molecular differences between adenocarcinoma and squamous cell carcinoma of the esophagous and also to determine molecular signatures specific for the aggressive nature of ESCC. Preliminary results indicate important differences in the pathways that are deregualted in the two forms of cancers. Work is currently underway 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.Identification and characterization of pancreatic cancer genes located within novel localized copy number alterations; Project funded by the Department of Science and Technology, Govt of India.

Pancreatic cancer is the fourth leading cause of cancer death in the United States and Europe and the incidence rates almost parallel mortality rates. The highly invasive and metastatic nature of this cancer makes it refractory to conventional treatment regimens. In a collaboration with Dr Jonathan R Pollack, Stanford University and Dr Anirban Maitra, Johns Hopkins University, we had earlier used aCGH and gene expression microarrays to identify novel pancreatic cancer genes.

In this project, using a combination of cell and molecular biological techniques, we have commenced the characterization of three novel regions of recurrent copy number alterations; a high level amplification located at 19q13, a homozygous deletion located at 6q25 and a homozygous deletion at 18q23. Results indicate that these regions harbor novel pancreatic cancer genes that play an important role in processes relevant to tumour progression including cell motility, chromatin remodeling and cell signaling.


4. Molecular genetic analyses of Familial Hypertrophic Cardiomyopathy in Andhra Pradesh;, a project funded by the Department of Biotechnology, Government of India, 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 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. We have commenced clinical and molecular genetic analysis of FHC patients from Andhra Pradesh. Our studies have revealed mutations in the MYH7 and MyBPC3 genes in several affected families. Results also indicate that modifier genes such as the ace as well as non-genetic factors including age and gender may play an important role in modulating the clinical presentation in patients. Current efforts are focused on 1) identification of mutations prevalent in patients in the local population in Andhra Pradesh, 2) characterization of rare and novel disease causing mutations, 3) establishing genotype-phenotype correlations and 4) providing efficient management to affected families through genetic counseling.

5. 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), Farber disease, Ectodermal dysplasia, Maple Syrup Urine Disease (MSUD), Lysosomal storage disorders 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 several novel mutations in EDA, Farber disease and MSUD patients. Characterization of novel mutations have improved our understanding of basic cellular phenomenon including nuclear splicing, protein folding, glycosylation etc.