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

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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 pretreatment 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, whereas 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 versus those with BRAF gains [HR, 2.86; 95% confidence interval (CI), 1.29–6.35; P ¼ 0.01] and in patients with low percentage versus those with a balanced BRAF mutant allele percentage (HR, 4.54; 95% CI, 1.33–15.53; P ¼ 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.

Original languageEnglish
Pages (from-to)1332-1340
Number of pages9
JournalMolecular Cancer Therapeutics
Volume17
Issue number6
DOIs
Publication statusPublished - Jun 1 2018

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Gene Dosage
Gene Frequency
Melanoma
Chromosomes, Human, Pair 7
Alleles
Confidence Intervals
Gene Amplification
Gene Deletion
Mutation Rate
Therapeutics
Diploidy
Disease-Free Survival
Chromosomes
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{b8394540076e4577a0ce952c8bad3a17,
title = "BRAF gene copy number and mutant allele frequency correlate with time to progression in metastatic melanoma patients treated with MAPK inhibitors",
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 pretreatment 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, whereas 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 versus those with BRAF gains [HR, 2.86; 95{\%} confidence interval (CI), 1.29–6.35; P ¼ 0.01] and in patients with low percentage versus those with a balanced BRAF mutant allele percentage (HR, 4.54; 95{\%} CI, 1.33–15.53; P ¼ 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.",
author = "Camilla Stagni and Carolina Zamuner and Lisa Elefanti and Tiziana Zanin and Bianco, {Paola Del} and Antonio Sommariva and Alessio Fabozzi and Jacopo Pigozzo and Simone Mocellin and Montesco, {Maria Cristina} and Vanna Chiarion-Sileni and {De Nicolo}, Arcangela and Chiara Menin",
year = "2018",
month = "6",
day = "1",
doi = "10.1158/1535-7163.MCT-17-1124",
language = "English",
volume = "17",
pages = "1332--1340",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
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TY - JOUR

T1 - BRAF gene copy number and mutant allele frequency correlate with time to progression in metastatic melanoma patients treated with MAPK inhibitors

AU - Stagni, Camilla

AU - Zamuner, Carolina

AU - Elefanti, Lisa

AU - Zanin, Tiziana

AU - Bianco, Paola Del

AU - Sommariva, Antonio

AU - Fabozzi, Alessio

AU - Pigozzo, Jacopo

AU - Mocellin, Simone

AU - Montesco, Maria Cristina

AU - Chiarion-Sileni, Vanna

AU - De Nicolo, Arcangela

AU - Menin, Chiara

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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 pretreatment 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, whereas 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 versus those with BRAF gains [HR, 2.86; 95% confidence interval (CI), 1.29–6.35; P ¼ 0.01] and in patients with low percentage versus those with a balanced BRAF mutant allele percentage (HR, 4.54; 95% CI, 1.33–15.53; P ¼ 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.

AB - 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 pretreatment 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, whereas 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 versus those with BRAF gains [HR, 2.86; 95% confidence interval (CI), 1.29–6.35; P ¼ 0.01] and in patients with low percentage versus those with a balanced BRAF mutant allele percentage (HR, 4.54; 95% CI, 1.33–15.53; P ¼ 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.

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U2 - 10.1158/1535-7163.MCT-17-1124

DO - 10.1158/1535-7163.MCT-17-1124

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VL - 17

SP - 1332

EP - 1340

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 6

ER -