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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Research Article

BRAF gene copy number and mutant allele frequency correlate with time to progression in metastatic melanoma patients treated with MAPK inhibitors.

Camilla Stagni, Carolina Zamuner, Lisa Elefanti, Tiziana Zanin, Paola Del Bianco, Antonio Sommariva, Alessio Fabozzi, Jacopo Pigozzo, Simone Mocellin, Maria Cristina Montesco, Vanna Chiarion-Sileni, Arcangela De Nicolo and Chiara Menin
Camilla Stagni
Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova
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Carolina Zamuner
Anatomy and Histology Unit, Veneto Institute of Oncology, IOV - IRCCS
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Lisa Elefanti
Diagnostic Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV - IRCCS
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Tiziana Zanin
Anatomy and Histology Unit, Veneto Institute of Oncology, IOV - IRCCS
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Paola Del Bianco
Clinical Trials and Biostatistics Unit, Veneto Institute of Oncology, IOV-IRCCS, Padova
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  • ORCID record for Paola Del Bianco
Antonio Sommariva
Surgical Oncology Unit, Veneto Institute of Oncology, IOV - IRCCS
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Alessio Fabozzi
Melanoma and Esophagus Oncology Unit, Veneto Institute of Oncology, IOV - IRCCS
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Jacopo Pigozzo
Melanoma and Esophagus Oncology Unit, Veneto Institute of Oncology, IOV - IRCCS
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Simone Mocellin
Surgical Oncology Unit, Veneto Institute of Oncology, IOV - IRCCS
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Maria Cristina Montesco
Anatomy and Histology Unit, Veneto Institute of Oncology, IOV - IRCCS
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Vanna Chiarion-Sileni
Melanoma and Esophagus Oncology Unit, Veneto Institute of Oncology, IOV - IRCCS
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Arcangela De Nicolo
Cancer Genomics Program, Veneto Institute of Oncology IOV - IRCCS
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Chiara Menin
Diagnostic Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV - IRCCS
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  • For correspondence: chiara.menin@iov.veneto.it
DOI: 10.1158/1535-7163.MCT-17-1124
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Abstract

Metastatic melanoma is characterized by complex genomic alterations including a high rate of mutations in driver genes and widespread deletions and amplifications encompassing various chromosome regions. Among them, chromosome 7 is frequently gained in BRAF mutant melanoma, inducing a mutant allele-specific imbalance. Although BRAF amplification is a known mechanism of acquired resistance to therapy with MAPK inhibitors, it is still unclear if BRAF copy number variation and BRAF mutant allele imbalance at baseline can be associated with response to treatment. In this study, we used a multimodal approach to assess BRAF copy number and mutant allele frequency in pre-treatment melanoma samples from 46 patients who received MAPK inhibitor-based therapy and we analyzed the association with progression free survival. We found that 65% patients displayed BRAF gains, often supported by chromosome 7 polysomy. In addition, we observed that 64% patients had a balanced BRAF mutant/wild-type allele ratio, while 14% and 23% patients had low and high BRAF mutant allele frequency, respectively. Notably, a significantly higher risk of progression was observed in patients with a diploid BRAF status vs. those with BRAF gains (HR = 2.86; 95% CI 1.29-6.35; p = 0.01) and in patients with low percentage vs. those with a balanced BRAF mutant allele percentage (HR = 4.54, 95% CI 1.33-15.53; p = 0.016). Our data suggest that quantitative analysis of the BRAF gene could be useful to select the melanoma patients who are most likely to benefit from therapy with MAPK inhibitors.

  • Received November 13, 2017.
  • Revision received February 7, 2018.
  • Accepted March 27, 2018.
  • Copyright ©2018, American Association for Cancer Research.
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Published OnlineFirst April 6, 2018
doi: 10.1158/1535-7163.MCT-17-1124

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BRAF gene copy number and mutant allele frequency correlate with time to progression in metastatic melanoma patients treated with MAPK inhibitors.
Camilla Stagni, Carolina Zamuner, Lisa Elefanti, Tiziana Zanin, Paola Del Bianco, Antonio Sommariva, Alessio Fabozzi, Jacopo Pigozzo, Simone Mocellin, Maria Cristina Montesco, Vanna Chiarion-Sileni, Arcangela De Nicolo and Chiara Menin
Mol Cancer Ther April 6 2018 DOI: 10.1158/1535-7163.MCT-17-1124

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BRAF gene copy number and mutant allele frequency correlate with time to progression in metastatic melanoma patients treated with MAPK inhibitors.
Camilla Stagni, Carolina Zamuner, Lisa Elefanti, Tiziana Zanin, Paola Del Bianco, Antonio Sommariva, Alessio Fabozzi, Jacopo Pigozzo, Simone Mocellin, Maria Cristina Montesco, Vanna Chiarion-Sileni, Arcangela De Nicolo and Chiara Menin
Mol Cancer Ther April 6 2018 DOI: 10.1158/1535-7163.MCT-17-1124
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Copyright 2016 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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