Cold Spring Harbor molecular case studies, volume 4, issue 2, pages a002535

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

Daniel R Owen 1, 2
Hui-Lee Wong 3
Melika Bonakdar 4
Martin P. Jones 4
Christopher Hughes 4
Gregg B. Morin 4, 5
Steve M. R. Jones 4, 5
Daniel J Renouf 3
Howard Lim 3
Janessa Laskin 4, 5
M. Marra 4, 5
Stephen Yip 1, 2
David F Schaeffer 1, 2
Show full list: 13 authors
2
 
2Department of Pathology & Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia V5Z 1M9, Canada
3
 
3Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4E63, Canada
4
 
4Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada
Publication typeJournal Article
Publication date2018-02-08
scimago Q2
SJR0.801
CiteScore3.2
Impact factor1.8
ISSN23732873, 23732865
General Medicine
Abstract

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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