title: Associations of Ki-ras proto-oncogene mutation and p53 gene overexpression in sporadic colorectal adenomas with demographic and clinicopathologic characteristics.
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 (>or=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 (>or=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 <or= 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.
authors.affiliation: Department of Medicine, Arizona Cancer Center, P.O. Box 245024, Tucson, AZ 85724, USA. jeinspahr@azcc.arizona.edu
authors.forename: Janine G
authors.initials: JG
authors.lastname: Einspahr
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Martinez
authors.forename: Ruiyun
authors.initials: R
authors.lastname: Jiang
authors.forename: Chiu-Hsieh
authors.initials: CH
authors.lastname: Hsu
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.forename: Achyut K
authors.initials: AK
authors.lastname: Bhattacharrya
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Ahnen
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Jacobs
authors.forename: P Scott
authors.initials: PS
authors.lastname: Houlihan
authors.forename: C Renee
authors.initials: CR
authors.lastname: Webb
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Hamilton
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018253:Adenoma, Villous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D003710:Demography; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas