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Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases

ERBB2 amplification has been identified in ∼5% of KRAS wild-type colorectal cancers (CRCs). A recent clinical trial showed response to HER2-directed therapy in a subset of ERBB2-amplified metastatic CRCs resistant to chemotherapy and EGFR-directed therapy. With the aim of better understanding mechan...

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Autores principales: Owen, Daniel R., Wong, Hui-li, Bonakdar, Melika, Jones, Martin, Hughes, Christopher S., Morin, Gregg B., Jones, Steven J.M., Renouf, Daniel J., Lim, Howard, Laskin, Janessa, Marra, Marco, Yip, Stephen, Schaeffer, David F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880263/
https://www.ncbi.nlm.nih.gov/pubmed/29438965
http://dx.doi.org/10.1101/mcs.a002535
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author Owen, Daniel R.
Wong, Hui-li
Bonakdar, Melika
Jones, Martin
Hughes, Christopher S.
Morin, Gregg B.
Jones, Steven J.M.
Renouf, Daniel J.
Lim, Howard
Laskin, Janessa
Marra, Marco
Yip, Stephen
Schaeffer, David F.
author_facet Owen, Daniel R.
Wong, Hui-li
Bonakdar, Melika
Jones, Martin
Hughes, Christopher S.
Morin, Gregg B.
Jones, Steven J.M.
Renouf, Daniel J.
Lim, Howard
Laskin, Janessa
Marra, Marco
Yip, Stephen
Schaeffer, David F.
author_sort Owen, Daniel R.
collection PubMed
description ERBB2 amplification has been identified in ∼5% of KRAS wild-type colorectal cancers (CRCs). A recent clinical trial showed response to HER2-directed therapy in a subset of ERBB2-amplified metastatic CRCs resistant to chemotherapy and EGFR-directed therapy. With the aim of better understanding mechanisms of resistance to HER2-directed and EGFR-directed therapies, we report the complete molecular characterization of two cases of ERBB2-amplified CRC. PCR-free whole-genome sequencing was used to identify mutations, copy-number alterations, structural variations, and losses of heterozygosity. ERBB2 copy number was also measured by fluorescence in situ hybridization. Single-stranded mRNA sequencing was used for gene expression profiling. Immunohistochemistry and protein mass spectrometry were used to quantify HER2 protein expression. The cases showed ERBB2 copy number of 86 and 92, respectively. Both cases were immunohistochemically positive for HER2 according to CRC-specific scoring criteria. Fluorescence in situ hybridization and protein mass spectrometry corroborated significantly elevated ERBB2 copy number and abundance of HER2 protein. Both cases were microsatellite stable and without mutation of RAS pathway genes. Additional findings included altered expression of PTEN, MET, and MUC1 and mutation of PIK3CA. The potential effects of the molecular alterations on sensitivity to EGFR and HER2-directed therapies were discussed. Identification of ERBB2 amplification in CRC is necessary to select patients who may respond to HER2-directed therapy. An improved understanding of the molecular characteristics of ERBB2-amplified CRCs and their potential mechanisms of resistance will be useful for future research into targeted therapies and may eventually inform therapeutic decision-making.
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spelling pubmed-58802632018-04-13 Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases Owen, Daniel R. Wong, Hui-li Bonakdar, Melika Jones, Martin Hughes, Christopher S. Morin, Gregg B. Jones, Steven J.M. Renouf, Daniel J. Lim, Howard Laskin, Janessa Marra, Marco Yip, Stephen Schaeffer, David F. Cold Spring Harb Mol Case Stud Research Report ERBB2 amplification has been identified in ∼5% of KRAS wild-type colorectal cancers (CRCs). A recent clinical trial showed response to HER2-directed therapy in a subset of ERBB2-amplified metastatic CRCs resistant to chemotherapy and EGFR-directed therapy. With the aim of better understanding mechanisms of resistance to HER2-directed and EGFR-directed therapies, we report the complete molecular characterization of two cases of ERBB2-amplified CRC. PCR-free whole-genome sequencing was used to identify mutations, copy-number alterations, structural variations, and losses of heterozygosity. ERBB2 copy number was also measured by fluorescence in situ hybridization. Single-stranded mRNA sequencing was used for gene expression profiling. Immunohistochemistry and protein mass spectrometry were used to quantify HER2 protein expression. The cases showed ERBB2 copy number of 86 and 92, respectively. Both cases were immunohistochemically positive for HER2 according to CRC-specific scoring criteria. Fluorescence in situ hybridization and protein mass spectrometry corroborated significantly elevated ERBB2 copy number and abundance of HER2 protein. Both cases were microsatellite stable and without mutation of RAS pathway genes. Additional findings included altered expression of PTEN, MET, and MUC1 and mutation of PIK3CA. The potential effects of the molecular alterations on sensitivity to EGFR and HER2-directed therapies were discussed. Identification of ERBB2 amplification in CRC is necessary to select patients who may respond to HER2-directed therapy. An improved understanding of the molecular characteristics of ERBB2-amplified CRCs and their potential mechanisms of resistance will be useful for future research into targeted therapies and may eventually inform therapeutic decision-making. Cold Spring Harbor Laboratory Press 2018-04 /pmc/articles/PMC5880263/ /pubmed/29438965 http://dx.doi.org/10.1101/mcs.a002535 Text en © 2018 Owen et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Owen, Daniel R.
Wong, Hui-li
Bonakdar, Melika
Jones, Martin
Hughes, Christopher S.
Morin, Gregg B.
Jones, Steven J.M.
Renouf, Daniel J.
Lim, Howard
Laskin, Janessa
Marra, Marco
Yip, Stephen
Schaeffer, David F.
Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases
title Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases
title_full Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases
title_fullStr Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases
title_full_unstemmed Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases
title_short Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases
title_sort molecular characterization of erbb2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880263/
https://www.ncbi.nlm.nih.gov/pubmed/29438965
http://dx.doi.org/10.1101/mcs.a002535
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