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Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer
  1. Michael Kloth1,
  2. Vanessa Ruesseler1,
  3. Christoph Engel2,
  4. Katharina Koenig1,
  5. Martin Peifer3,
  6. Erika Mariotti3,
  7. Helen Kuenstlinger1,
  8. Alexandra Florin1,
  9. Ursula Rommerscheidt-Fuss1,
  10. Ulrike Koitzsch1,
  11. Claudia Wodtke1,
  12. Frank Ueckeroth1,
  13. Stefanie Holzapfel4,
  14. Stefan Aretz4,
  15. Peter Propping4,
  16. Markus Loeffler2,
  17. Sabine Merkelbach-Bruse1,
  18. Margarete Odenthal1,
  19. Nicolaus Friedrichs1,
  20. Lukas Carl Heukamp1,
  21. Thomas Zander5,
  22. Reinhard Buettner1
  1. 1Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany
  2. 2Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  3. 3Department of Translational Genomics, Centre for Molecular Medicine Cologne, Cologne, Germany
  4. 4Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
  5. 5Department of Internal Medicine I, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany
  1. Correspondence to Dr Thomas Zander, Department of Internal Medicine I, Centre for Integrated Oncology, University Hospital Cologne, Kerpenerstr. 62, Cologne 50924, Germany; Thomas.Zander{at}uk-koeln.de

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 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.

  • CANCER GENETICS
  • CANCER SYNDROMES
  • COLORECTAL NEOPLASM
  • GENE TARGETING
  • MOLECULAR ONCOLOGY

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