Department of Pathology & Laboratory Medicine
GASTROINTESTINAL DISEASES:
Dr. Fenoglio-Preiser heads a team of investigators involved in addressing questions relating to gastrointestinal cancer. This group consists of Drs. Fenoglio-Preiser, Stemmermann, and Noffsinger. Although the group works interchangeably and on all the projects, functionally, Dr. Noffsinger is responsible for the majority of the work in ulcerative colitis and Dr. Fenoglio-Preiser directs the investigations in sporadic colon cancer and gastric cancer. Translational activities with respect to ulcerative colitis have as their specific aim to identify markers that predict increased risk for the development of colorectal cancer in the setting of chronic inflammatory bowel disease so that these markers can be used to stratify patients in surveillance programs. The rationale for the investigations is that there is a subset of cancers which are not preceded by histological evidence of dysplasia which remain undetected until they have evolved into full-blown invasive cancers. It is not clear that they have a histologically recognizable precursor. The group has identified a potential molecular alteration which may identify such patients. p53 mutations are present in histologically nonneoplastic mucosa of such patients who lack overlying dysplastic changes.The inflammatory bowel disease studies are being done on a patient base which stems from the excellence of the Surgery Department in treating this disease. For this reason, Drs. Fischer and Nussbaum are involved in many of these collaborations.
Current gastric and colonic studies focus on three questions:
1) are there molecular abnormalities present in tumors that allow one
to "upstage" or "downstage" an individual tumor,
2) are there are biomarkers that predict chemosensitivity and radiosensitivity,
and
3) are there molecular changes that predispose to the development
of malignancy.
The investigators are fortunate to have access to a large group of patients who are enrolled in large national cooperative group clinical. Therefore, these patients are uniformly diagnosed, treated, and evaluated. Dr. Fenoglio-Preiser heads the NCI-funded repository for the Southwest Oncology Group. The repository has tissue banked on over 800 gastrointestinal tumors derived from patients enrolled on national clinical protocols.
One group of studies relates to the molecular biology of gastric cancer. Gastric carcinomas come in two major forms and the molecular phenotypes of each may differ considerably. As a result, the response to therapy and the prognostic factors in each type of cancer may differ considerably. The studies are aimed at analysis of genes involved in the cell proliferative and cell death pathways in an effort to develop predictive markers for therapeutic responsiveness. For that reason, an analysis of thymidilate synthase activity, p53 mutational analysis, growth factor analysis, and analysis of genes such as BAX and the mismatch repair genes is likely to provide insights into the two distinct types of gastric cancers. To date, we have found that the only secure way of documenting the presence of mutated p53 genes is to sequence the gene both in the mutational hotspot area as well as outside of it, since mutations occur in exons 4, 9, and 10, areas outside the hotspot region. Additionally, a significant number of patients have a polymorphism of exon 4, the significance of which is being currently studied. Preliminary studies are also being undertaken in order to develop data for a larger study involving the interaction of H. pylori with the p53 gene products. In collaboration with Dr. Kim, the group is attempting to generate a new classification scheme for gastric cancer.
We have also analyzed both esophageal and gastric cancers for the presence of Epstein-Barr virus within the tumor cell genomes. Viral genetic sequences are present within gastric cancers but not in esophageal cancers and their presence correlates with the proliferative activity of the tumors.
Studies are about to begin on rectal carcinomas to determine whether the genes that become inactivated in these tumors resemble those in the proximal colorectum. Additionally, genes whose products function in response to radiation will be evaluated. Alterations in the p53 gene, ras gene, and DCC gene will be analyzed to determine if they represent independent predictors of patient survival and/or therapeutic response. Thymidilate synthase, the enzyme target of the drug 5-FU, will also be evaluated in these tumors to determine their relationship to responsiveness to 5-FU.
Studies in collaboration with Dr. Lowy from the Department of Surgery aim to determine molecular markers of therapeutic response in a neoadjuvant trial of GE junction cancers and to look at loss of E-cadherin in pancreatic cancers.
Finally, discussions are underway with the National Cancer Institute to initiate molecular analyses in patients with pancreatic and colon cancers who will be treated with farnysl inhibitors to determine their molecular phenotype as well as the role of this phenotype in patient response to the farnysl inhibitors.
With respect to molecular staging, it is known that patients with stage II colorectal cancers with loss of DCC gene function behave as stage III tumors.
Dr. Stemmermann's research focuses on defining risk factors for cancer development. A major question involves the definition of environmental versus genetic influences in cancer development. His research involves a cohort of Japanese men (N=8006) living in Hawaii during the years 1940-42. These men were examined in the years 1965-68 in order to establish baseline physical, chemical, dietary, and socioeconomic parameters to assess the impact of western life styles upon their disease experiences. The men were born between 1910 and 1991. Their living and deceased relatives have been identified. Serum samples have been obtained from each subject and these have been stored at -70?C. Paraffin blocks have been obtained from cancers that have developed subsequent to examination. These are available for studies designed to correlate cancer risk factors with tumor markers and for identification of gene rearrangements in tumors from men with known exposures to carcinogens. The block collection includes nonneoplastic tissues, and samples of cancer precursors as well. The collection includes more than 600 cases of gastrointestinal and pulmonary tumors, but has samples from other tumor sites as well. Dr. Fenoglio-Preiser remains involved in a 15-year-old NCI study addressing the differences in colon cancer in Blacks versus Whites.
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