title: One-hit effects in cancer: altered proteome of morphologically normal colon crypts in familial adenomatous polyposis.
abstract: We studied patients with Familial Adenomatous Polyposis (FAP) because they are virtually certain to develop colon cancer, and because much is known about the causative APC gene. We hypothesized that the inherited heterozygous mutation itself leads to changes in the proteome of morphologically normal crypts and the proteins that changed may represent targets for preventive and therapeutic agents. We determined the differential protein expression of morphologically normal colon crypts of FAP patients versus those of individuals without the mutation, using two-dimensional gel electrophoresis, mass spectrometry, and validation by two-dimensional gel Western blotting. Approximately 13% of 1,695 identified proteins were abnormally expressed in the morphologically normal crypts of APC mutation carriers, indicating that a colon crypt cell under the one-hit state is already abnormal. Many of the expression changes affect pathways consistent with the function of the APC protein, including apoptosis, cell adhesion, cell motility, cytoskeletal organization and biogenesis, mitosis, transcription, and oxidative stress response. Thus, heterozygosity for a mutant APC tumor suppressor gene alters the proteome of normal-appearing crypt cells in a gene-specific manner, consistent with a detectable one-hit event. These changes may represent the earliest biomarkers of colorectal cancer development, potentially leading to the identification of molecular targets for cancer prevention.
authors.affiliation: Division of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA. AT_Yeung@fccc.edu
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Yeung
authors.forename: Bhavinkumar B
authors.initials: BB
authors.lastname: Patel
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Li
authors.forename: Steven H
authors.initials: SH
authors.lastname: Seeholzer
authors.forename: Renata A
authors.initials: RA
authors.lastname: Coudry
authors.forename: Harry S
authors.initials: HS
authors.lastname: Cooper
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bellacosa
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Boman
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Samuel
authors.initials: S
authors.lastname: Litwin
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ross
authors.forename: Peggy
authors.initials: P
authors.lastname: Conrad
authors.forename: James A
authors.initials: JA
authors.lastname: Crowell
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Alfred
authors.initials: A
authors.lastname: Knudson
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D016000:Cluster Analysis; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D017491:Genes, APC; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018384:Oxidative Stress; D020543:Proteome / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D020543:Proteome
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