title: Genetic signatures of high- and low-risk aberrant crypt foci in a mouse model of sporadic colon cancer.
abstract: To determine whether cancer risk is related to histopathological features of preneoplastic aberrant crypt foci (ACF), gene expression analysis was performed on ACF from two mouse strains with differing tumor sensitivity to the colonotropic carcinogen, azoxymethane. ACF from sensitive A/J mice were considered at high risk, whereas ACF from resistant AKR/J mice were considered at low risk for tumorigenesis. A/J and AKR/J mice received weekly injections of azoxymethane (10 mg/kg body weight), and frozen colon sections were prepared 6 weeks later. Immunohistochemistry was performed using biomarkers associated with colon cancer, including adenomatous polyposis coli, beta-catenin, p53, c-myc, cyclin D1, and proliferating cell nuclear antigen. Hyperplastic ACF, dysplastic ACF, microadenomas, adjacent normal-appearing epithelium, and vehicle-treated colons were laser captured, and RNA was linearly amplified (LCM-LA) and subjected to cDNA microarray-based expression analysis. Patterns of gene expression were identified using adaptive centroid algorithm. ACF from low- and high-risk colons were not discriminated by immunohistochemistry, with the exception of membrane staining of beta-catenin. To develop genetic signatures that predict cancer risk, LCM-LA RNA from ACF was hybridized to cDNA arrays. Of 4896 interrogated genes, 220 clustered into six broad clusters. A total of 226 and 202 genes was consistently altered in lesions from A/J and AKR/J mice, respectively. Although many alterations were common to both strains, expression profiles stratified high- and low- risk lesions. These data demonstrate that ACF with distinct tumorigenic potential have distinguishing molecular features. In addition to providing insight into colon cancer promotion, our data identify potential biomarkers for determining colon cancer risk in humans.
authors.affiliation: Center for Molecular Medicine and Program in Colorectal Cancer, University of Connecticut Health Center, Farmington, Connecticut 06030-3101, USA.
authors.forename: Prashant R
authors.initials: PR
authors.lastname: Nambiar
authors.forename: Masako
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Rishi
authors.initials: R
authors.lastname: Gupta
authors.forename: Evelyn
authors.initials: E
authors.lastname: Cheung
authors.forename: Ali
authors.initials: A
authors.lastname: Firouzi
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Ma
authors.forename: Christopher
authors.initials: C
authors.lastname: Flynn
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.forename: Kishore
authors.initials: K
authors.lastname: Guda
authors.forename: Joel
authors.initials: J
authors.lastname: Levine
authors.forename: Rajiv
authors.initials: R
authors.lastname: Raja
authors.forename: Luke
authors.initials: L
authors.lastname: Achenie
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006965:Hyperplasia; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor