Colorectal cancer is the second leading cause of cancer deaths in the United States. Adjuvant chemotherapy with 5-fluorouracil (5-FU) and levamisole leads to improved survival of patients with resected Dukes colonic cancer, but patient selection is based mainly on stage and no markers predicting response are available. Our Bowel Tumor Working Group at Johns Hopkins has found that allelic deletions of chromosome 17p (p53 gene) and l8q (DcC gene) are associated with poorer prognosis. We propose to support a Study Team with the Eastern Cooperative Oncology Group (ECOG) for large-scale evaluation of molecular genetic alterations as markers for patient selection and response to adjuvant therapy.
Specific Aim #1 : Determine the utility of allelic deletions of 17p and l8q and immunocytochemical expression of p53 and DCC gene product in identifying Dukes' B2 and B3 colonic cancer with poor prognosis. We will assess the deletions and gene products in banked disaggregated tumors from ECOG Protocol EST 5283 (phase III protocol for Dukes' B2 and B3 colonic carcinoma: observation arm) and relate the results to survival.
Specific Aim #2 : Determine the utility of allelic deletions of 17p and l8q and immunocytochemical expression of p53 and DCC gene product in identifying Dukes' c colonic cancer responsive to 5-FU and levamisole. We will assess the deletions and gene products in banked disaggregated tumors from ECOG Protocol EST 1290 (phase III protocol for Dukes' c colonic carcinoma: 5-FU/levamisole arm) and relate results to survival.
Specific Aim #3 : Determine the utility of allelic deletions of 17p and l8q and immunohistochemical expression of p53 and DCC gene product in identifying Dukes' B2 and c colonic carcinoma responsive to perioperative 5-FU and adjuvant 5-FU/levamisole. We will assess the deletions and gene products in microdissected frozen tumor from ECOG Protocol E 1292 perioperative Adjuvant Colon Protocol) and relate the results to survival.
Specific Aim #4 : Compare the prognostic value of the genetic changes to other prognostic markers including DNA aneuploidy and S phase by flow cytometry (ECOG Protocol EST 4287) and sialosyl-Tn antigen expression.
| Ribic, Christine M; Sargent, Daniel J; Moore, Malcolm J et al. (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247-57 |
| Watanabe, T; Wu, T T; Catalano, P J et al. (2001) Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 344:1196-206 |
