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, 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 journalArticleScientificpeer-review

    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 pro-Odes a growth advantage to this subset of MSI colon tumors. [Cancer Res 2009;69(19):7811-8]"
    Original languageEnglish
    JournalCancer Research
    Volume69
    Issue number29
    Pages (from-to)7811-7818
    Number of pages8
    ISSN0008-5472
    DOIs
    Publication statusPublished - 2009
    MoE publication typeA1 Journal article-refereed

    Fields of Science

    • 311 Basic medicine

    Cite this

    Yuan, Ziqiang ; Shin, Joongho ; 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. 29. pp. 7811-7818.
    @article{4e3fe453f8fb4d889647bf8b820338e4,
    title = "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",
    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 pro-Odes a growth advantage to this subset of MSI colon tumors. [Cancer Res 2009;69(19):7811-8]{"}",
    keywords = "311 Basic medicine",
    author = "Ziqiang Yuan and Joongho Shin and Andrew Wilson and Sanjay Goel and Yi-He Ling and Naseem Ahmed and Higinio Dopeso and Minaxi Jhawer and Shannon Nasser and Cristina Montagna and Kenneth Fordyce and Augenlicht, {Leonard H} and Aaltonen, {Lauri A} and Diego Arango and Weber, {Thomas K} and Mariadason, {John M}",
    year = "2009",
    doi = "10.1158/0008-5472.CAN-09-0986",
    language = "English",
    volume = "69",
    pages = "7811--7818",
    journal = "Cancer Research",
    issn = "0008-5472",
    publisher = "American Association for Cancer Research",
    number = "29",

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    Yuan, Z, Shin, J, Wilson, A, Goel, S, Ling, Y-H, Ahmed, N, Dopeso, H, Jhawer, M, Nasser, S, Montagna, C, Fordyce, K, Augenlicht, LH, Aaltonen, LA, Arango, D, Weber, TK & Mariadason, JM 2009, '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', Cancer Research, vol. 69, no. 29, pp. 7811-7818. https://doi.org/10.1158/0008-5472.CAN-09-0986

    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; 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. 29, 2009, p. 7811-7818.

    Research output: Contribution to journalArticleScientificpeer-review

    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 - Yuan, Ziqiang

    AU - Shin, Joongho

    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

    Y1 - 2009

    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 pro-Odes a growth advantage to this subset of MSI colon tumors. [Cancer Res 2009;69(19):7811-8]"

    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 pro-Odes a growth advantage to this subset of MSI colon tumors. [Cancer Res 2009;69(19):7811-8]"

    KW - 311 Basic medicine

    U2 - 10.1158/0008-5472.CAN-09-0986

    DO - 10.1158/0008-5472.CAN-09-0986

    M3 - Article

    VL - 69

    SP - 7811

    EP - 7818

    JO - Cancer Research

    JF - Cancer Research

    SN - 0008-5472

    IS - 29

    ER -