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KRAS Mutant Allele-Specific Imbalance (MASI) assessment in routine samples of patients with metastatic colorectal cancer
  1. Umberto Malapelle1,
  2. Roberta Sgariglia1,
  3. Alfonso De Stefano2,
  4. Claudio Bellevicine1,
  5. Elena Vigliar1,
  6. Dario de Biase3,
  7. Romina Sepe4,5,
  8. Pierlorenzo Pallante4,5,
  9. Chiara Carlomagno2,
  10. Giovanni Tallini3,
  11. Giancarlo Troncone1
  1. 1Department of Public Health, University of Naples Federico II, Naples, Italy
  2. 2Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoles, Italy
  3. 3Department of Medicine (DIMES)—Anatomic Pathology Unit, Bellaria Hospital, University of Bologna, Bologna, Italy
  4. 4CNR/IEOS, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
  5. 5Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples Federico II, Naples, Italy
  1. Correspondence to Professor Giancarlo Troncone, Department of Public Health, University of Naples Federico II, via Sergio Pansini 5, Naples I-80131, Italy; giancarlo.troncone{at}unina.it

Abstract

Aims Patients with colorectal cancer harbouring KRAS mutations do not respond to antiepidermal growth factor receptor (anti-EGFR) therapy. Community screening for KRAS mutation selects patients for treatment. When a KRAS mutation is identified by direct sequencing, mutant and wild type alleles are seen on the sequencing electropherograms. KRAS mutant allele-specific imbalance (MASI) occurs when the mutant allele peak is higher than the wild type one. The aims of this study were to verify the rate and tissue distribution of KRAS MASI as well as its clinical relevance.

Methods A total of 437 sequencing electropherograms showing KRAS exon 2 mutation was reviewed and in 30 cases next generation sequencing (NGS) was also carried out. Five primary tumours were extensively laser capture microdissected to investigated KRAS MASI tissue spatial distribution. KRAS MASI influence on the overall survival was evaluated in 58 patients. In vitro response to anti-EGFR therapy in relation to different G13D KRAS MASI status was also evaluated.

Results On the overall, KRAS MASI occurred in 58/436 cases (12.8%), being more frequently associated with G13D mutation (p=0.05) and having a heterogeneous tissue distribution. KRAS MASI detection by Sanger Sequencing and NGS showed 94% (28/30) concordance. The longer overall survival of KRAS MASI negative patients did not reach statistical significance (p=0.08). In cell line model G13D KRAS MASI conferred resistance to cetuximab treatment.

Conclusions KRAS MASI is a significant event in colorectal cancer, specifically associated with G13D mutation, and featuring a heterogeneous spatial distribution, that may have a role to predict the response to EGFR inhibitors. The foreseen implementation of NGS in community KRAS testing may help to define KRAS MASI prognostic and predictive significance.

  • COLON
  • MOLECULAR BIOLOGY
  • TUMOUR MARKERS

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