Sarah Mange

Risk factors and Molecular Pathology of Colorectal Cancer in Egyptian Patients

ABSTRACT: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer-related mortality in the United States. Cancer rates are generally lower in Egypt than in developed countries. While CRC is only the fifth leading cause of cancer-related mortality in Egypt, the country experiences an unusually high burden of disease in patients under the age of 40, with more than one third of cases in this age group. A study of lifestyle, occupational, and reproductive factors in Egypt found that a history of pesticide exposure and frequently eating foods directly from farms were significantly associated with a higher risk of CRC, while prolonged lactation and increased parity in women were inversely associated with CRC. Industrial exposures were significantly more common in younger Egyptian patients. Research on the molecular characteristic of Egyptian colorectal cancers has demonstrated a high proportion of carcinomas located in the rectum, a low frequency of mutation in the proto-oncogene K-ras, and a high frequency of microsatellite instability high (MSI-H) tumors due to the silencing of DNA mismatch repair genes. Overexpression of the mutated gene product of tumor suppressor p53 is more common in Egyptian MSI-H colorectal cancers than among Western cancers, and MSI-H tumors were more commonly seen in older Egyptian patients rather than those under the age of 40. In contrast to MSI-H tumors associated with hereditary non-polyposis colorectal cancer, MSI-H was not explained by germline mutation of the mismatch repair gene hMSH2 and the majority of these patients did not demonstrate a family history of CRC. Studies have shown that DNA hypermethylation of the promoters of many genes results in transcriptional silencing and is associated with CRC. The CpG island methylator phenotype (CIMP) can be measured by examining the percentage of methylation in a panel of genes that are unmethylated in normal tissue. The relationship of CIMP to the other molecular descriptors of Egyptian CRC has not been explored on a large scale, and linking the pathogenesis of CRC to environmental exposures and lifestyle factors could guide cancer control and prevention efforts. We would like to expand research in these areas to achieve the following:

Specific Aims:

  • To describe the molecular pathology of CRC in Egyptian patients in terms of P53 and K-ras mutation, microsatellite instability, and the CpG island methylator phenotype.
  • To explore the significance of the associations between various lifestyle factors and environmental exposures and the molecular pathology of colorectal cancer in Egypt.