Universität zu Köln

Kloth, Michael, Ruesseler, Vanessa, Engel, Christoph ORCID: 0000-0002-7247-282X, Koenig, Katharina, Peifer, Martin ORCID: 0000-0002-5243-5503, Mariotti, Erika, Kuenstlinger, Helen, Florin, Alexandra, Rommerscheidt-Fuss, Ursula, Koitzsch, Ulrike, Wodtke, Claudia, Ueckeroth, Frank, Holzapfel, Stefanie, Aretz, Stefan ORCID: 0000-0002-5228-1890, Propping, Peter, Loeffler, Markus, Merkelbach-Bruse, Sabine, Odenthal, Margarete, Friedrichs, Nicolaus, Heukamp, Lukas Carl, Zander, Thomas and Buettner, Reinhard (2016). Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer. Gut, 65 (8). S. 1296 - 1306. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-3288

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Abstract

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 BRAF(V600E); however, no consistent data exist regarding targeted treatment approaches in BRAF(wt) 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 BRAF(wt) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kloth, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruesseler, Vanessa UNSPECIFIED UNSPECIFIED UNSPECIFIED Engel, Christoph UNSPECIFIED orcid.org/0000-0002-7247-282X UNSPECIFIED Koenig, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Peifer, Martin UNSPECIFIED orcid.org/0000-0002-5243-5503 UNSPECIFIED Mariotti, Erika UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuenstlinger, Helen UNSPECIFIED UNSPECIFIED UNSPECIFIED Florin, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Rommerscheidt-Fuss, Ursula UNSPECIFIED UNSPECIFIED UNSPECIFIED Koitzsch, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Wodtke, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Ueckeroth, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Holzapfel, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Aretz, Stefan UNSPECIFIED orcid.org/0000-0002-5228-1890 UNSPECIFIED Propping, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Loeffler, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Merkelbach-Bruse, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED Friedrichs, Nicolaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Heukamp, Lukas Carl UNSPECIFIED UNSPECIFIED UNSPECIFIED Zander, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-268484
DOI:	10.1136/gutjnl-2014-309026
Journal or Publication Title:	Gut
Volume:	65
Number:	8
Page Range:	S. 1296 - 1306
Date:	2016
Publisher:	BMJ PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1468-3288
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COMPREHENSIVE MOLECULAR CHARACTERIZATION; MICROSATELLITE INSTABILITY; MISMATCH REPAIR; COLON-CANCER; GENE; ADENOCARCINOMA; TRANSFORMATION; TUMORIGENESIS; METHYLATION; CARCINOMAS Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26848