Einspahr Janine G, Martinez Maria Elena, Jiang Ruiyun, Hsu Chiu-Hsieh, Rashid Asif, Bhattacharrya Achyut K, Ahnen Dennis J, Jacobs Elizabeth T, Houlihan P Scott, Webb C Renee, Alberts David S, Hamilton Stanley R
Department of Medicine, Arizona Cancer Center, P.O. Box 245024, Tucson, AZ 85724, USA.
Cancer Epidemiol Biomarkers Prev. 2006 Aug;15(8):1443-50. doi: 10.1158/1055-9965.EPI-06-0144.
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.
在结直肠癌发生过程中，Ki-ras原癌基因突变通常在腺瘤-腺癌序列的早期出现，而p53基因突变则与晚期进展为癌有关。我们评估了926名参加III期复发预防试验的个体的1093个基线散发性结直肠腺瘤的人口统计学和临床病理特征与Ki-ras突变及p53基因产物过表达之间的关系。在14.7%的个体中发现了Ki-ras突变，在7.0%的检测个体中发现了p53过表达。多变量分析发现，年龄较大、直肠部位以及绒毛状组织学与Ki-ras突变独立相关。患有高级别腺瘤（≥1 cm或高级别异型增生或绒毛状组织学）的个体发生Ki-ras突变的可能性高4倍[比值比（OR）为3.96；95%置信区间（CI）为2.54 - 6.18]。密码子12的Ki-ras突变以及G-to-A转换类型在老年个体中更常见，而G-to-T颠换在直肠腺瘤中比在结肠腺瘤中更常见。多变量分析显示，息肉既往史（P = 0.03）与p53过表达呈负相关。大腺瘤大小（≥1 cm）、高级别异型增生和绒毛状组织学与p53过表达独立相关，其中与高级别腺瘤的相关性最强（OR为7.20；95% CI为3.01 - 17.22）。患有Ki-ras突变腺瘤的个体更有可能过表达p53（OR为2.46；95% CI为1.36 - 4.46），并且94.8%同时具有这两种改变的腺瘤被归类为高级别腺瘤（P≤0.0001）。我们的大型横断面研究支持了Ki-ras和p53在腺瘤进展中的作用，并表明它们的分子发病机制因解剖位置、年龄以及息肉既往史所证明的黏膜易感性而有所不同。
