RT Journal Article
SR Electronic
T1 Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1296
OP 1305
DO 10.1136/gutjnl-2014-309026
VO 65
IS 8
A1 Michael Kloth
A1 Vanessa Ruesseler
A1 Christoph Engel
A1 Katharina Koenig
A1 Martin Peifer
A1 Erika Mariotti
A1 Helen Kuenstlinger
A1 Alexandra Florin
A1 Ursula Rommerscheidt-Fuss
A1 Ulrike Koitzsch
A1 Claudia Wodtke
A1 Frank Ueckeroth
A1 Stefanie Holzapfel
A1 Stefan Aretz
A1 Peter Propping
A1 Markus Loeffler
A1 Sabine Merkelbach-Bruse
A1 Margarete Odenthal
A1 Nicolaus Friedrichs
A1 Lukas Carl Heukamp
A1 Thomas Zander
A1 Reinhard Buettner
YR 2016
UL http://gut.bmj.com/content/65/8/1296.abstract
AB Objective Microsatellite instability (MSI) is detected in approximately 15% of all colorectal cancers (CRC) and virtually in all cases with Lynch syndrome. The MSI phenotype is caused by dysfunctional mismatch repair (MMR) and leads to accumulation of DNA replication errors. Sporadic MSI CRC often harbours BRAFV600E; however, no consistent data exist regarding targeted treatment approaches in BRAFwt MSI CRC.Design Mutations and quantitative MSI were analysed by deep sequencing in 196 formalin fixed paraffin embedded (FFPE) specimens comprising Lynch and Lynch-like CRCs from the German Hereditary Nonpolyposis Colorectal Cancer registry. Functional relevance of recurrent ERBB2/HER2 mutations was investigated in CRC cell lines using reversible and irreversible HER-targeting inhibitors, EGFR-directed antibody cetuximab, HER2-directed antibody trastuzumab and siRNA-mediated ERBB2/HER2 knockdown.Results Quantification of nucleotide loss in non-coding mononucleotide repeats distinguished microsatellite status with very high accuracy (area under curve=0.9998) and demonstrated progressive losses with deeper invasion of MMR-deficient colorectal neoplasms (p=0.008). Characterisation of BRAFwt MSI CRC revealed hot-spot mutations in well-known oncogenic drivers, including KRAS (38.7%), PIK3CA (36.5%), and ERBB2 (15.0%). L755S and V842I substitutions in ERBB2 were highly recurrent. Functional analyses in ERBB2-mutated MSI CRC cell lines revealed a differential response to HER-targeting compounds and superiority of irreversible pan-HER inhibitors.Conclusions We developed a high-throughput deep sequencing approach for concomitant MSI and mutational analyses in FFPE specimens. We provided novel insights into clinically relevant alterations in MSI CRC and a rationale for targeting ERBB2/HER2 mutations in Lynch and Lynch-like CRC.