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

Yuan Ziqiang, Shin Joongho, 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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7811-7818
Number of pages8
JournalCancer Research
Volume69
Issue number19
DOIs
StatePublished - Oct 1 2009

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Microsatellite Instability
3' Untranslated Regions
Epidermal Growth Factor Receptor
Colonic Neoplasms
Cell Line
Mutation
Colorectal Neoplasms
Colon
Dinucleotide Repeats
erbB-1 Genes
RNA Stability
Epigenomics
Microsatellite Repeats
Adenosine
Introns
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Ziqiang, Yuan; Joongho, Shin; Wilson, Andrew; Goel, Sanjay; Ling, Yi He; Ahmed, Naseem; Dopeso, Higinio; Jhawer, Minaxi; Nasser, Shannon; Montagna, Cristina; Fordyce, Kenneth; Augenlicht, Leonard H.; Aaltonen, Lauri A.; Arango, Diego; Weber, Thomas K.; Mariadason, John M.

In: Cancer Research, Vol. 69, No. 19, 01.10.2009, p. 7811-7818.

Research output: Contribution to journalArticle

Ziqiang, Yuan ; Joongho, Shin ; Wilson, Andrew ; Goel, Sanjay ; Ling, Yi He ; Ahmed, Naseem ; Dopeso, Higinio ; Jhawer, Minaxi ; Nasser, Shannon ; Montagna, Cristina ; Fordyce, Kenneth ; Augenlicht, Leonard H. ; Aaltonen, Lauri A. ; Arango, Diego ; Weber, Thomas K. ; Mariadason, John M. / 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. In: Cancer Research. 2009 ; Vol. 69, No. 19. pp. 7811-7818.
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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.

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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.

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