Date of Award

4-1998

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Dr. Susan Stapleton

Second Advisor

Dr. Leonard Ginsberg

Third Advisor

Dr. David Reinhold

Fourth Advisor

Dr. Anthony Senagore

Abstract

The successful treatment of colorectal cancer depends upon the ability of staging systems to identify patients who are at risk for recurrence. The currently used systems fail in a significant number of patients. Multiple attempts have been made to improve upon these systems in order to provide better treatment for at-risk patients.

A variety of oncogenes and tumor suppressor genes have been implicated in colorectal cancer. Mutations in one of these, K-ras, occur in 40-60% of colorectal carcinomas. However, the relationship between specific mutations and clinical outcome is unclear.

The purpose of this study was to determine whether or not K-ras mutational status of tumors from 97 colorectal cancer patients was associated with survival, and to determine whether or not the K-ras mutational status of regional lymph nodes could be used as a staging tool.

The group was divided into four cohorts according to survival (less than five or greater than ten years) and modified Dukes’ classification (B2 and C2). The author assessed techniques for DNA extraction and mutation detection. Tumor DNA was screened for K-ras mutations using mutation-specific DNA amplification, followed by gel electrophoresis in a 96-well array. Dukes’ B2 patients with mutations were further analyzed to determine whether or not the same mutations could be identified in their lymph nodes.

Complete data was obtained for 89 patients (91.8%). Mutations were detected in 49.4% of tumors (44/89). Analysis of the mutations identified a group of 11 patients with concurrent mutations in codons 12 and 13, which was associated with long-term survival. Mutational analysis of lymph nodes from Dukes B2 patients with mutation-positive tumors revealed an 80% (16/20) incidence of the same mutations in regional lymph nodes. None of the four patients with mutation-free lymph nodes developed recurrence compared to 37.5% (6/16) with K-ras positive lymph nodes.

The presence of concurrent mutations in codons 12 and 13 of the K-ras gene was a positive prognostic indicator in this group of patients. Mutational analysis of lymph nodes identifies high-risk patients who should be considered for additional treatment. Therefore, K-ras mutational analysis should be considered for molecular staging of colorectal cancer.

Access Setting

Dissertation-Open Access

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