TY - JOUR
T1 - 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
AU - Ziqiang, Yuan
AU - Joongho, Shin
AU - Wilson, Andrew
AU - Goel, Sanjay
AU - Ling, Yi He
AU - Ahmed, Naseem
AU - Dopeso, Higinio
AU - Jhawer, Minaxi
AU - Nasser, Shannon
AU - Montagna, Cristina
AU - Fordyce, Kenneth
AU - Augenlicht, Leonard H.
AU - Aaltonen, Lauri A.
AU - Arango, Diego
AU - Weber, Thomas K.
AU - Mariadason, John M.
PY - 2009/10/1
Y1 - 2009/10/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-09-0986
DO - 10.1158/0008-5472.CAN-09-0986
M3 - Article
C2 - 19789347
AN - SCOPUS:70350215709
SN - 0008-5472
VL - 69
SP - 7811
EP - 7818
JO - Cancer research
JF - Cancer research
IS - 19
ER -