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Low-Level c-myc Amplification in Human Colonic Carcinoma Cell Lines and Tumors: A Frequent, p53-independent Mutation Associated with Improved Outcome in a Randomized Multi-institutional Trial¹

Department of Oncology, Albert Einstein Cancer Center, Bronx, New York 10467 [L. H. A., S. W., G. C., C. R., B. G. H.]; Dana-Farber Cancer Center, Boston, Massachusetts 02115 [L. R.]; University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [A. S. M., S. P.]; Northwestern University, Chicago, Illinois 60611 [A. B.]; and University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104 [D. H.]

Human colonic cancer is associated with multiple genetic deletions, mutations, and alterations in gene expression; in contrast, gene amplification has not been recognized as a prominent characteristic of human colonic tumors. Although the c-myc gene is overexpressed in approximately 70% of human colonic cancers, previous studies have not detected frequent gene amplification or rearrangement of c-myc in these tumors, although such amplification has been reported in chemically induced rodent colon cancer and quantitative analysis of gene copy number has shown the gene to be amplified at a low level in mucinous and poorly differentiated human colon carcinomas. Using rigorously controlled blot methodology, we have established that the c-myc gene, located at 8q21, exhibited amplification of 87% to 35-fold in 7 of 10 human colonic carcinoma cell lines. This was highly significant even at a low level of amplification in HT29 cells (P < 0.0001). Cytogenetic analysis by G-banding did not detect aneuploidy involving chromsome 8q, suggesting that the amplification for the c-myc gene on 8q was relatively specific, and this was consistent with a lack of amplification detected for the c-mos gene on 8q24, which was assayed similarly. The same methodology then revealed amplification of c-myc from 1.5-fold to 5-fold in 32% of tumors from 149 patients entered into a multi-institutional Phase III study of adjuvant therapy for colon cancer. c-myc status was not related to time to recurrence or death, but low levels of c-myc amplification identified a subset of patients who showed a statistically significant increase in disease-free survival, and a corresponding trend to longer overall survival, in response to adjuvant therapy with 5-fluorouracil plus levamisole. Presence of c-myc amplification was not related to incidence of p53 mutations.

¹ This study was supported in part by United States Public Health Service Grants CA53446, CA57694, and P30-CA13330 and by the John F. Dunn Foundation.

² To whom requests for reprints should be addressed, at Department of Oncology, Albert Einstein Cancer Center, 111 East 210th Street, Bronx, NY 10467. Phone: (718) 920-4663; Fax: (718) 882-4464.

Received 11/ 6/96. Accepted 3/ 1/97.

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