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 trial

Leonard H. Augenlicht*, Scott Wadler, Georgia Corner, Christine Richards, Louise Ryan, Asha S. Multani, Sen Pathak, Al B Benson III, Daniel Haller, Barbara G. Heerdt

*Corresponding author for this work

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

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 chromosome 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.

Original languageEnglish (US)
Pages (from-to)1769-1775
Number of pages7
JournalCancer Research
Volume57
Issue number9
StatePublished - May 1 1997

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Tumor Cell Line
Colonic Neoplasms
myc Genes
Carcinoma
Mutation
Gene Amplification
mos Genes
Neoplasms
Levamisole
HT29 Cells
Gene Dosage
Gene Rearrangement
Sequence Deletion
Cytogenetic Analysis
Aneuploidy
Fluorouracil
Disease-Free Survival
Rodentia
Colon
Chromosomes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Augenlicht, Leonard H. ; Wadler, Scott ; Corner, Georgia ; Richards, Christine ; Ryan, Louise ; Multani, Asha S. ; Pathak, Sen ; Benson III, Al B ; Haller, Daniel ; Heerdt, Barbara G. / 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 trial. In: Cancer Research. 1997 ; Vol. 57, No. 9. pp. 1769-1775.
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title = "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 trial",
abstract = "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 chromosome 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.",
author = "Augenlicht, {Leonard H.} and Scott Wadler and Georgia Corner and Christine Richards and Louise Ryan and Multani, {Asha S.} and Sen Pathak and {Benson III}, {Al B} and Daniel Haller and Heerdt, {Barbara G.}",
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language = "English (US)",
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Augenlicht, LH, Wadler, S, Corner, G, Richards, C, Ryan, L, Multani, AS, Pathak, S, Benson III, AB, Haller, D & Heerdt, BG 1997, '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 trial', Cancer Research, vol. 57, no. 9, pp. 1769-1775.

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 trial. / Augenlicht, Leonard H.; Wadler, Scott; Corner, Georgia; Richards, Christine; Ryan, Louise; Multani, Asha S.; Pathak, Sen; Benson III, Al B; Haller, Daniel; Heerdt, Barbara G.

In: Cancer Research, Vol. 57, No. 9, 01.05.1997, p. 1769-1775.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Low-level c-myc amplification in human colonic carcinoma cell lines and tumors

T2 - A frequent, p53-independent mutation associated with improved outcome in a randomized multi-institutional trial

AU - Augenlicht, Leonard H.

AU - Wadler, Scott

AU - Corner, Georgia

AU - Richards, Christine

AU - Ryan, Louise

AU - Multani, Asha S.

AU - Pathak, Sen

AU - Benson III, Al B

AU - Haller, Daniel

AU - Heerdt, Barbara G.

PY - 1997/5/1

Y1 - 1997/5/1

N2 - 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 chromosome 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.

AB - 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 chromosome 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.

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