Supplementary Figure 3 from 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
posted on 2023-03-30, 18:50authored byZiqiang Yuan, Joongho Shin, Andrew Wilson, Sanjay Goel, Yi-He Ling, Naseem Ahmed, Higinio Dopeso, Minaxi Jhawer, Shannon Nasser, Cristina Montagna, Kenneth Fordyce, Leonard H. Augenlicht, Lauri A. Aaltonen, Diego Arango, Thomas K. Weber, John M. Mariadason
Supplementary Figure 3 from 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
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ARTICLE ABSTRACT
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]