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One-Hit Effects in Cancer: Altered Proteome of Morphologically Normal Colon Crypts in Familial Adenomatous Polyposis

Divisions of ¹ Basic Science, ² Medical Science, and ³ Population Science, Fox Chase Cancer Center, and ⁴ Division of Genetic and Preventive Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; ⁵ University of California at San Francisco, San Francisco, California; and ⁶ Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Anthony T. Yeung, Room R404, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497. Phone: 215-728-2488; Fax: 215-728-3647; E-mail: AT_Yeung{at}fccc.edu.

Key Words: Familial Adenomatous Polyposis • APC • tumor suppressor • colon crypts • proteomics

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. [Cancer Res 2008;68(18):7579–86]