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Yeung AT , Patel BB , Li XM , Seeholzer SH , Coudry RA , Cooper HS , Bellacosa A , Boman BM , Zhang T , Litwin S , Ross EA , Conrad P , Crowell JA , Kopelovich L , Knudson A
One-hit effects in cancer: altered proteome of morphologically normal colon crypts in familial adenomatous polyposis
Cancer Res. 2008 Sep 15;68(18) :7579-86
PMID: 18794146    PMCID: PMC2562578   
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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.
Yeung, Anthony T Patel, Bhavinkumar B Li, Xin-Ming Seeholzer, Steven H Coudry, Renata A Cooper, Harry S Bellacosa, Alfonso Boman, Bruce M Zhang, Tao Litwin, Samuel Ross, Eric A Conrad, Peggy Crowell, James A Kopelovich, Levy Knudson, Alfred CA119242/CA/NCI NIH HHS/United States DK063014/DK/NIDDK NIH HHS/United States N01 CN015103/CN/NCI NIH HHS/United States N01 CN043309/CN/NCI NIH HHS/United States N01-CN-15103/CN/NCI NIH HHS/United States N01-CN-43309/CN/NCI NIH HHS/United States P30CA006927/CA/NCI NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Cancer research Cancer Res. 2008 Sep 15;68(18):7579-86.