1. Molecular Characterization of early-onset rectal cancer; funded by a Fogarty International Research Collaboration award, National Institutes of Health, USA (2008 to 2011).

Colorectal cancer (CRC) is the third most common cancer worldwide and is perhaps the best understood of all cancers. Although rapid advances have been made in patient management and therapy for most forms of CRC, our understanding of sporadic early-onset rectal cancer (RC) is limited which interestingly forms the predominant subtype among Indian CRC patients. More importantly, rectal tumors are known to be associated with a rapid metastatic spread and poor survival. We have performed the first comprehensive molecular characterization of rectal tumour samples from India. Surprisingly, a significantly high proportion of early onset rectal tumours (as against late-onset tumours) do not harbour either of the two canonical tumorigenesis pathways namely Wnt signaling and mismatch repair defect that drive a majority of colorectal tumours; a difference not seen in colon tumors. Interestingly however, the tumors exhibit extensive chromosomal instability, as determined through microarray-based comparative genomic hybridization. Efforts are currently underway, using next generation RNA sequencing and genome-wide transcript profiling through microarrays, to understand the biology of this unique CRC subtype. In parallel, our comprehensive studies on the familial cancer syndrome Hereditary Non-Polyposis Colorectal Cancer has revealed involvement of novel genes among Indian patients.

2. Identification and characterization of pancreatic cancer genes located within novel localized copy number alterations; funded by Department of Science and Technology (2006-2009) and Department of Biotechnology.

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 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 copy number alterations in pancreatic cancer. Using a combination of cell and molecular biological approaches, we have commenced the characterization of two novel tumor suppressor genes located within novel homozygous deletions at 6q25 and 18q23. Results indicate that the genes may play an important role in processes relevant to tumour progression including chromatin remodeling and cell motility.

3. "Identification of novel esophageal squamous cell carcinoma (ESCC) genes by using a combination of array based CGH and gene expression microarrays"; funded by the Department of Biotechnology.

Esophageal squamous cell carcinoma (ESCC), the predominant form of esophageal cancer in India, is an aggressive cancer associated with high mortality. In contrast, esophageal, adenocarcinoma (EA) is more common in the West. We first performed a detailed molecular and clinico-pathological comparison of ESCC and EA tumour samples. The frequency of EGFR activation and Wnt signaling as against p53 inactivation were significantly different between the two subtypes. Interestingly, the differences were also replicated in adenosquamous mixed tumor samples. We are currently working to identify and characterize genetic events important for ESCC progression. We have commenced aCGH based identification of deregulated genes in ESCC with the aim of identifying novel drug targets.

4. Clinical and molecular genetic analysis of squamous cell carcinoma of the tongue, funded by Indian Council for Medical Research (ICMR).>

Tongue cancer accounts for about 6-8% of all cancers in India and about a fourth of all Head and Neck cancers. Among Head and Neck cancers, tongue cancer appears to have the highest mortality rate, due to its propensity to metastasize rapidly. Tongue cancer is unique in head and neck cancer because of its relatively higher incidence at relative young age and a comparatively high incidence in nonsmokers. We have performed the first comprehensive molecular pathological analysis of squamous cell carcinoma of the mobile tongue occurring in India. Results reveal interesting features with respect to status of EGFR, P53, microsatellite instability and loss of heterozygosity of specific chromosomal loci. We plan to perform genome wide DNA copy number alterations and transcript profiles to study specific genetic alterations occurring in tumors harboring a wild type P53.

5. Molecular analysis of genetic disorders; funded from CDFD core funds.

We have initiated molecular genetic screening for several genetic disorders including Familial Hypertrophic Cardiomyopathy, Hypohidrotic/Anhidrotic Ectodermal Dysplasia, Phenylketonuria, Farber Disease, beta Thalassemia, Maple Syrup Urine Disease, etc. The work has revealed a unique mutation profile among Indian patients. More importantly, we have catalogues several mutations that appear to effect the gene transcript rather than the expressed protein. Work is currently underway to characterization these mutations in order to improve our understanding of basic cellular phenomenon including nuclear splicing and nonsense mediated decay.