Abstract A7: Identification of novel genetic alterations in GI tumors using whole-genome profiling

A7

In our previous studies, we identified novel pancreatic cancer genes using a combination of array-based comparative genomic hybridization (aCGH) and gene expression microarrays (Neoplasia, 2007 and Kwei and PLOS Genet, 2008). In the current study, we have used a multipronged approach to address two important GI cancers prevalent in India. Colorectal cancer (CRC) is a major health problem worldwide and is usually an age-related disease. A small proportion of patients present at an early age due to familial cancer syndromes. Surprisingly, there appears to be a high proportion of patients in India who present at an early age without a family background and succumb to aggressive metastatic tumors. Using immunohistochemistry, mutation screening and microsatellite instability analysis of more than 150 samples, we show that Wnt signaling, a hallmark of CRC in the West, is not a major feature in a majority of young patients in India unlike older patients. There does not appear to be a significant difference between the two categories of CRC patients in other parameters including gender, lifestyle, diet, tumor location, frequency of microsatellite instability, and Loss of Heterozygosity at the BRCAI locus. In addition, we have identified several novel mutations in the APC gene in Wnt positive tumors. Determination of genome-wide copy number alterations and transcript profiles is expected to delineate the genetic aberrations that may lead to CRC in the young in India.

Squamous cell carcinoma of the esophagus (ESCC) is common in India and Asia but rare in the West, as against esophagus adenocarcinoma which is common in the West but not in India. ESCC is a poorly studied highly aggressive cancer with survival rates below 15% in most populations. We have carried out molecular analysis of about 75 ESCC samples and 26 adenocarcinoma samples using archived as well as fresh resected tumors. Results indicate that unlike the ESCC samples, a significant proportion of adenocarcinoma samples exhibited an activated Wnt signaling pathway. Inactivation of p53 however appeared to be a common event in both Esophagus cancer subtypes. Analysis of copy number alterations using array-based CGH has revealed a recurrent amplification at 10q21 in ESCC samples. The amplification harbored genes that exhibited comparably altered transcript levels, as determined by array-based transcript profiling. We are also carrying out molecular analyses of mixed adeno-squamous tumors of the esophagus; results are expected to reveal whether the squamous and adeno components have an independent origin or vice versa.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A7.