Associations of Ki-ras proto-oncogene mutation and p53 gene overexpression in sporadic colorectal adenomas with demographic and clinicopathologic characteristics

Janine G Einspahr, Maria Elena Martinez, Ruiyun Jiang, Chiu-Hsieh Hsu, Achyut K. Bhattacharrya, Dennis J. Ahnen, Elizabeth T Jacobs, P. Scott Houlihan, C. Renee Webb, David S Alberts, Stanley R. Hamilton

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Abstract

In colorectal tumorigenesis, Ki-ras proto-oncogene mutation often occurs early in the adenoma-adenocarcinoma sequence, whereas mutation of the p53 gene is associated with late progression to carcinoma. We evaluated the relationship of demographic and clinicopathologic characteristics to Ki-ras mutation and p53 gene product overexpression in 1,093 baseline sporadic colorectal adenomas from 926 individuals enrolled in a phase III recurrence prevention trial. Ki-ras mutation was found in 14.7% of individuals and p53 overexpression was found in 7.0% of those tested. Multivariate analysis found older age, rectal location, and villous histology to be independently associated with Ki-ras mutation. Individuals with an advanced adenoma (≥1 cm or high-grade dysplasia or villous histology) had a 4-fold higher likelihood of Ki-ras mutation [odds ratios (OR), 3.96; 95% confidence intervals (CI), 2.54-6.18]. Ki-ras mutations in codon 12 and of the G-to-A transition type were more frequent in older individuals, whereas G-to-T transversion was more frequent in rectal adenomas than in the colon. Multivariate analysis showed that previous history of a polyp (P = 0.03) was inversely associated with p53 overexpression. Large adenoma size (≥1 cm), high-grade dysplasia, and villous histology were independently associated with p53 overexpression, with the strongest association for advanced adenomas (OR, 7.20; 95% CI, 3.01-17.22). Individuals with a Ki-ras mutated adenoma were more likely to overexpress p53 (OR, 2.46; 95% CI, 1.36-4.46), and 94.8% of adenomas with both alterations were classified as advanced (P ≤ 0.0001). Our large cross-sectional study supports the role of both Ki-ras and p53 in the progression of adenomas and shows that their molecular pathogenesis differs by anatomic location, age, and mucosal predisposition as evidenced by previous history of a polyp.

Original languageEnglish (US)
Pages (from-to)1443-1450
Number of pages8
JournalCancer Epidemiology Biomarkers and Prevention
Volume15
Issue number8
DOIs
StatePublished - Aug 2006

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ras Genes
Proto-Oncogenes
p53 Genes
Adenoma
Demography
Mutation
Histology
Odds Ratio
Confidence Intervals
Polyps
Multivariate Analysis
Codon
Colon
Carcinogenesis
Adenocarcinoma
Cross-Sectional Studies
Carcinoma
Recurrence

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Associations of Ki-ras proto-oncogene mutation and p53 gene overexpression in sporadic colorectal adenomas with demographic and clinicopathologic characteristics. / Einspahr, Janine G; Martinez, Maria Elena; Jiang, Ruiyun; Hsu, Chiu-Hsieh; Bhattacharrya, Achyut K.; Ahnen, Dennis J.; Jacobs, Elizabeth T; Houlihan, P. Scott; Webb, C. Renee; Alberts, David S; Hamilton, Stanley R.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 15, No. 8, 08.2006, p. 1443-1450.

Research output: Contribution to journalArticle

Einspahr, Janine G ; Martinez, Maria Elena ; Jiang, Ruiyun ; Hsu, Chiu-Hsieh ; Bhattacharrya, Achyut K. ; Ahnen, Dennis J. ; Jacobs, Elizabeth T ; Houlihan, P. Scott ; Webb, C. Renee ; Alberts, David S ; Hamilton, Stanley R. / Associations of Ki-ras proto-oncogene mutation and p53 gene overexpression in sporadic colorectal adenomas with demographic and clinicopathologic characteristics. In: Cancer Epidemiology Biomarkers and Prevention. 2006 ; Vol. 15, No. 8. pp. 1443-1450.
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abstract = "In colorectal tumorigenesis, Ki-ras proto-oncogene mutation often occurs early in the adenoma-adenocarcinoma sequence, whereas mutation of the p53 gene is associated with late progression to carcinoma. We evaluated the relationship of demographic and clinicopathologic characteristics to Ki-ras mutation and p53 gene product overexpression in 1,093 baseline sporadic colorectal adenomas from 926 individuals enrolled in a phase III recurrence prevention trial. Ki-ras mutation was found in 14.7{\%} of individuals and p53 overexpression was found in 7.0{\%} of those tested. Multivariate analysis found older age, rectal location, and villous histology to be independently associated with Ki-ras mutation. Individuals with an advanced adenoma (≥1 cm or high-grade dysplasia or villous histology) had a 4-fold higher likelihood of Ki-ras mutation [odds ratios (OR), 3.96; 95{\%} confidence intervals (CI), 2.54-6.18]. Ki-ras mutations in codon 12 and of the G-to-A transition type were more frequent in older individuals, whereas G-to-T transversion was more frequent in rectal adenomas than in the colon. Multivariate analysis showed that previous history of a polyp (P = 0.03) was inversely associated with p53 overexpression. Large adenoma size (≥1 cm), high-grade dysplasia, and villous histology were independently associated with p53 overexpression, with the strongest association for advanced adenomas (OR, 7.20; 95{\%} CI, 3.01-17.22). Individuals with a Ki-ras mutated adenoma were more likely to overexpress p53 (OR, 2.46; 95{\%} CI, 1.36-4.46), and 94.8{\%} of adenomas with both alterations were classified as advanced (P ≤ 0.0001). Our large cross-sectional study supports the role of both Ki-ras and p53 in the progression of adenomas and shows that their molecular pathogenesis differs by anatomic location, age, and mucosal predisposition as evidenced by previous history of a polyp.",
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AU - Hsu, Chiu-Hsieh

AU - Bhattacharrya, Achyut K.

AU - Ahnen, Dennis J.

AU - Jacobs, Elizabeth T

AU - Houlihan, P. Scott

AU - Webb, C. Renee

AU - Alberts, David S

AU - Hamilton, Stanley R.

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