PT  - JOURNAL ARTICLE
AU  - Michael Kloth
AU  - Vanessa Ruesseler
AU  - Christoph Engel
AU  - Katharina Koenig
AU  - Martin Peifer
AU  - Erika Mariotti
AU  - Helen Kuenstlinger
AU  - Alexandra Florin
AU  - Ursula Rommerscheidt-Fuss
AU  - Ulrike Koitzsch
AU  - Claudia Wodtke
AU  - Frank Ueckeroth
AU  - Stefanie Holzapfel
AU  - Stefan Aretz
AU  - Peter Propping
AU  - Markus Loeffler
AU  - Sabine Merkelbach-Bruse
AU  - Margarete Odenthal
AU  - Nicolaus Friedrichs
AU  - Lukas Carl Heukamp
AU  - Thomas Zander
AU  - Reinhard Buettner
TI  - Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer
AID  - 10.1136/gutjnl-2014-309026
DP  - 2016 Aug 01
TA  - Gut
PG  - 1296--1305
VI  - 65
IP  - 8
4099  - http://gut.bmj.com/content/65/8/1296.short
4100  - http://gut.bmj.com/content/65/8/1296.full
SO  - Gut2016 Aug 01; 65
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.