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Sequence Alterations of Insulin-like Growth Factor Binding Protein 3 in Neoplastic and Normal Gastrointestinal Tissues¹

Department of Medicine, Gastrointestinal Division [T. Z., A. S. F., D. K., J. Y., R. F. S., S. W., K. N. S., J. M. A., S. J. M.], Greenebaum Cancer Center [S. J. M.], Molecular Biology Graduate Program [K. N. S., S. J. M.], and Department of Pathology [D. K., S. J. M.], University of Maryland School of Medicine and Baltimore Veterans Affairs Hospital, Baltimore, Maryland 21201

Insulin-like growth factor binding protein 3 (IGFBP-3) is an important regulator of normal and malignant cell growth. It modulates the mitogenic effects of insulin-like growth factors (IGFs) by inhibiting growth through mechanisms both dependent on and independent of IGF binding. IGF-I and IGF-II levels are regulated by binding to the IGF-II receptor, which is inactivated by mutation in human gastrointestinal (GI) tumors. We have previously demonstrated elevated IGF-II ligand expression in IGF-II receptor-mutant GI tumors, implicating the IGF signaling system in GI tumorigenesis. Therefore, to investigate the potential involvement of IG-FBP-3 in human GI carcinogenesis, direct DNA sequencing of exons 1–4 and intron-exon boundaries of the IGFBP-3 gene was performed in 10 colorectal cancers, 10 gastric cancers, and 10 esophageal cancers. Four distinct sequence alterations were identified: (a) in one gastric and one esophageal tumor, an A to C transversion occurred at nucleotide 5795 (CACCCC), leading to a HisPro substitution at codon 179; (b) a second esophageal tumor had a C to T transition at nucleotide 8291 (ACCATC), leading to a ThrIle substitution at codon 277 of IG-FBP-3; (c) one alteration comprised a G to C transversion in exon 1 at nucleotide 2132 (GGGGCG), leading to a GlyAla substitution at codon 32 in two gastric cancers, seven esophageal cancers, and nine colon cancers; and (d) a C to G transversion located 17 nucleotides from the 3' splice site in intron 1 was observed in three colon cancers and four esophageal cancers. All of these DNA sequence alterations were present in matched normal DNA from the same subjects, which suggests that some or all of them may represent polymorphisms. However, we cannot exclude the possibility that the germ-line nonconservative amino acid substitutions predicted to occur as a result of these alterations result in subtle changes to IGFBP-3 protein function and a predisposition to developing GI malignancy.

¹ Supported by USPHS Grants CA77057, CA78843, DK47717, CA67497, and DK53620 and the Office of Medical Research, Department of Veterans Affairs. A. S. F. is the recipient of NIH Grant F32-DK09886.

² To whom requests for reprints should be addressed, at University of Maryland N3W62, 22 South Greene Street, Baltimore, MD 21201. Fax: (410) 328-6559; E-mail: smeltzer@medicine.ab.umd.edu.

Received 7/29/98. Accepted 9/17/98.

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