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An A13 Repeat within the 3'-Untranslated Region of Epidermal Growth Factor Receptor (EGFR) Is Frequently Mutated in Microsatellite Instability Colon Cancers and Is Associated with Increased EGFR Expression

Departments of ¹ Surgery and Molecular Genetics and ² Pathology, Albert Einstein College of Medicine; ³ Department of Oncology, Montefiore Medical Center, Bronx, New York; ⁴ Molecular Biology and Biochemistry Research Center, Barcelona, Spain; ⁵ Computational Decision Science Group, IBM USA, Burlington, Vermont; and ⁶ Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

Requests for reprints: John M. Mariadason, Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Austin Health, Level 7, Harold Stokes Building, 145-163 Studley Road, Heidelberg, Victoria 3084, Australia. Phone: 61-3-9496-3068; Fax: 61-3-9496-5334; E-mail: john.mariadason{at}ludwig.edu.au or Thomas K. Weber, VA New York Harbor Health Care System, Brooklyn Campus 112, 800 Poly Place, Brooklyn, NY 11209. Phone: 718-630-3706; E-mail: thomas.weber2{at}va.gov.

Key Words: EGFR • MSI • colon cancer • mutation • 3'-UTR

Colorectal cancers (CRC) with microsatellite instability (MSI) have clinical, pathologic, genetic, and epigenetic features distinct from microsatellite-stable CRC. Examination of epidermal growth factor receptor (EGFR) mRNA and protein expression levels in a panel of colon cancer cell lines identified strong expression of EGFR in multiple cell lines with MSI. Although no relationship between EGFR overexpression and the length of a CA dinucleotide repeat in intron 1 was observed, a variant A13/A14 repeat sequence within the 3'-untranslated region (3'-UTR) of the EGFR gene was identified, which was mutated by either mononucleotide or dinucleotide adenosine deletions in 64% of MSI cell lines and 69% of MSI colon tumors. Using a Tet-Off system, we show that this mutation increases EGFR mRNA stability in colon cancer cells, providing a mechanistic basis for EGFR overexpression in MSI colon cancer cell lines. To determine whether this mutation is a driver or a bystander event in MSI colon cancer, we examined the effect of pharmacologic and molecular inhibition of EGFR in EGFR 3'-UTR mutant MSI cell lines. Cell lines with an EGFR 3'-UTR mutation and that were wild-type (WT) for downstream signaling mediators in the Ras/BRAF and PIK3CA/PTEN pathways were sensitive to EGFR inhibition, whereas those harboring mutations in these signaling mediators were not. Furthermore, in cell lines WT for downstream signaling mediators, those with EGFR 3'-UTR mutations were more sensitive to EGFR inhibition than EGFR 3'-UTR WT cells, suggesting that this mutation provides a growth advantage to this subset of MSI colon tumors. [Cancer Res 2009;69(19):7811–8]