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Carcinogenesis Advance Access published online on February 12, 2006
Carcinogenesis, doi:10.1093/carcin/bgi354
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received November 8, 2005
Revised January 10, 2006
Accepted January 23, 2006

CANCER BIOLOGY

Loss of heterozygosity in human aberrant crypt foci (ACF), a putative precursor of colon

Liping Luo 1, Gong-Qing Shen 2, Karen A. Stiffler 1, Qing K. Wang 2, Thomas G. Pretlow 1, and Theresa P. Pretlow 1 *

1 Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
2 Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA

* To whom correspondence should be addressed.
Theresa P. Pretlow, E-mail: theresa.pretlow{at}case.edu


  Abstract

Aberrant crypt foci, the earliest neoplastic lesions of the colon, have genetic and epigenetic alterations. Loss of heterozygosity (LOH) of tumor suppressor gene loci is seen in most colon cancers, but it is not known how early in tumorigenesis this takes place. Nine microsatellite markers close to specific genes, i.e., APC (5q21), PTPRJ (11p11), p53 (17p13) and DCC (18q21), were analyzed in 32 ACF and samples of normal crypts from the same 28 patients. Six losses of heterozygosity were found in 5 of 32 ACF: 4 losses of heterozygosity were at 11p11, the location of the gene for protein tyrosine phosphatase receptor type J (PTPRJ) and of a second independent region of deletion; the others were at 5q21 and 18q21. Microsatellite instability (MSI) with markers for a single locus was found in 4 of 32 ACF. All the observed allelic alterations (LOH and MSI) were in 8 of 32 ACF. The finding of loss of heterozygosity in aberrant crypt foci with normal expressions of adenomatous polyposis coli and beta-catenin proteins suggests that loss of heterozygosity can occur very early in colon neoplasia and perhaps even before APC mutations. The finding of 3 of 4 of the losses of heterozygosity at 11p11 for PTPRJ and half of all the losses of heterozygosity in this study at PTPRJ suggest this gene plays a role early in colon neoplasia.

Keywords: aberrant crypt foci (ACF); human colon tumorigenesis; loss of heterozygosity (LOH); chromosomal instability (CIN); microsatellite instability (MSI).
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