title: Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kloth
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ruesseler
authors.affiliation: Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Koenig
authors.affiliation: Department of Translational Genomics, Centre for Molecular Medicine Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.affiliation: Department of Translational Genomics, Centre for Molecular Medicine Cologne, Cologne, Germany.
authors.forename: Erika
authors.initials: E
authors.lastname: Mariotti
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Helen
authors.initials: H
authors.lastname: Kuenstlinger
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Florin
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Rommerscheidt-Fuss
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Koitzsch
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wodtke
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Ueckeroth
authors.affiliation: Institute of Human Genetics, University Hospital Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Holzapfel
authors.affiliation: Institute of Human Genetics, University Hospital Bonn, Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
authors.affiliation: Institute of Human Genetics, University Hospital Bonn, Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.affiliation: Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Merkelbach-Bruse
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Margarete
authors.initials: M
authors.lastname: Odenthal
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Lukas Carl
authors.initials: LC
authors.lastname: Heukamp
authors.affiliation: Department of Internal Medicine I, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zander
authors.affiliation: Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D018929:Cell Culture Techniques; D000068818:Cetuximab / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D053843:DNA Mismatch Repair; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000071185:Pharmacogenomic Testing / Q000379:methods; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: CANCER GENETICS; CANCER SYNDROMES; COLORECTAL NEOPLASM; GENE TARGETING; MOLECULAR ONCOLOGY