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.
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.
Departments of Surgery and Molecular Genetics and Pathology, Albert Einstein College of Medicine, New York, USA.
Ziqiang
Z
Yuan
Joongho
J
Shin
Andrew
A
Wilson
Sanjay
S
Goel
Yi-He
YH
Ling
Naseem
N
Ahmed
Higinio
H
Dopeso
Minaxi
M
Jhawer
Shannon
S
Nasser
Cristina
C
Montagna
Kenneth
K
Fordyce
Leonard H
LH
Augenlicht
Lauri A
LA
Aaltonen
Diego
D
Arango
Thomas K
TK
Weber
John M
JM
Mariadason
D020413:3' Untranslated Regions; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics*; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D005784:Gene Amplification; D018773:Genes, erbB-1; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D053842:Microsatellite Instability; D009154:Mutation; D011061:Poly A / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid; D043244:Ribonuclease III / Q000037:antagonists & inhibitors / Q000235:genetics; D017384:Sequence Deletion
D020413:3' Untranslated Regions; D012333:RNA, Messenger; D011061:Poly A; D066246:ErbB Receptors; D043244:Ribonuclease III