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BRAF Gene Copy Number and Mutant Allele Frequency Correlate With Published OnlineFirst April 6, 2018; DOI: 10.1158/1535-7163.MCT-17-1124 Companion Diagnostic, Pharmacogenomic, and Cancer Biomarkers Molecular Cancer Therapeutics BRAF Gene Copy Number and Mutant Allele Frequency Correlate with Time to Progression in Metastatic Melanoma Patients Treated with MAPK Inhibitors Camilla Stagni1, Carolina Zamuner2, Lisa Elefanti3, Tiziana Zanin2, Paola Del Bianco4, Antonio Sommariva5, Alessio Fabozzi6, Jacopo Pigozzo6, Simone Mocellin5, Maria Cristina Montesco2,Vanna Chiarion-Sileni6, Arcangela De Nicolo7, and Chiara Menin3 Abstract Metastatic melanoma is characterized by complex genomic found that 65% patients displayed BRAF gains, often supported alterations, including a high rate of mutations in driver genes by chromosome 7 polysomy. In addition, we observed that and widespread deletions and amplifications encompassing 64% patients had a balanced BRAF-mutant/wild-type allele various chromosome regions. Among them, chromosome 7 is ratio, whereas 14% and 23% patients had low and high BRAF frequently gained in BRAF-mutant melanoma, inducing a mutant allele frequency, respectively. Notably, a significantly mutant allele–specificimbalance.AlthoughBRAF amplification higher risk of progression was observed in patients with a is a known mechanism of acquired resistance to therapy with diploid BRAF status versus those with BRAF gains [HR, 2.86; MAPK inhibitors, it is still unclear if BRAF copy-number var- 95% confidence interval (CI), 1.29–6.35; P ¼ 0.01] and in iation and BRAF mutant allele imbalance at baseline can be patients with low percentage versus those with a balanced BRAF associated with response to treatment. In this study, we used a mutant allele percentage (HR, 4.54; 95% CI, 1.33–15.53; P ¼ multimodal approach to assess BRAF copy number and mutant 0.016). Our data suggest that quantitative analysis of the BRAF allele frequency in pretreatment melanoma samples from 46 genecouldbeusefultoselectthemelanomapatientswhoare patients who received MAPK inhibitor–based therapy, and we most likely to benefit from therapy with MAPK inhibitors. analyzed the association with progression-free survival. We Mol Cancer Ther; 1–9. Ó2018 AACR. Introduction have also been reported (COSMIC, http://www.sanger.ac.uk/ cosmic; refs. 3, 4). In recent years, the advent of selective Approximately 50% of cutaneous melanomas carry a B-Raf inhibitors of the MAPK pathway (i.e., BRAF and MEK inhibi- proto-oncogene, serine/threonine kinase (BRAF)mutation tors) has improved both the overall survival and the progres- that leads to constitutive activation of the MAPK pathway (1, sion-free survival (PFS) of BRAF V600–mutated (BRAFmut) 2). In more than 80% of cases, the mutation causes a valine to metastatic melanoma patients. After initial response, however, glutamic acid, less frequently, a valine to lysine, substitution at the majority of patients invariably experience the onset codon 600 (p.V600E and p.V600K, respectively). Rarer muta- of resistance, which limits long-term treatment effectiveness tions, including BRAF p.V600D, p.V600R, and p.V600_K601E, (5–9). In some cases, disease progression is immediate, occur- ring within 3 months (10). Therefore, the identification of 1Oncology and Immunology Section, Department of Surgery, Oncology and biomarkers that predict response to therapy is a prerequisite fi Gastroenterology, University of Padua, Padua, Italy. 2Anatomy and Histology for patient strati cation and treatment selection. Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 3Diagnostic BRAF gene amplification is described as one of the main Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV mechanisms of acquired resistance on BRAF inhibitor–based 4 - IRCCS, Padua, Italy. Clinical Trials and Biostatistics Unit, Veneto Institute of therapy (with or without MEK inhibitors) supporting reactivation Oncology IOV - IRCCS, Padua, Italy. 5Surgical Oncology Unit, Veneto Institute of 6 of the MAPK pathway (hence tumor cell proliferation) that leads Oncology IOV - IRCCS, Padua, Italy. Melanoma and Esophagus Oncology Unit, BRAF Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 7Cancer Genomics to relapse. A higher number of gene copies has been detected Program, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. in specimens from patients at disease progression compared with baseline biopsies (11–14). An increased BRAF gene copy number Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). has also been reported both in pretreatment specimens from metastatic melanoma patients who did not respond to therapy A. De Nicolo and C. Menin share senior authorship of this article. and in MAPK inhibitor (MAPKi)–resistant cell lines (15, 16). Corresponding Author: Chiara Menin, Veneto Institute of Oncology IOV - IRCCS, Thus, it is still debated if BRAF amplification is an acquired via Gattamelata 64, 35128 Padua, Italy. Phone: 39-0498215882; Fax: 39- mechanism of resistance, which develops de novo in the tumor 0498072854; E-mail: [email protected] cells to overcome BRAF inhibition, or if it can also play a role doi: 10.1158/1535-7163.MCT-17-1124 as an intrinsic mechanism when detected in the tumor prior to Ó2018 American Association for Cancer Research. MAPKi exposure. www.aacrjournals.org OF1 Downloaded from mct.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst April 6, 2018; DOI: 10.1158/1535-7163.MCT-17-1124 Stagni et al. A high rate of chromosome instability is a hallmark of macrodissected to enrich the tumor cell population. DNA was melanoma. It is also known that copy-number variation (CNV) extracted using the QIAmp DNA micro/mini Kit (Qiagen) or the becomes more pronounced with progression from in situ to MagNA Pure Compact Instrument (Roche Diagnostics) according metastatic melanoma. Cutaneous melanoma is characterized to the manufacturer's instructions. by a pattern of copy-number alterations that typically include chromosome 1, 6, and 7 gains and chromosome 9 and 10 losses Real-time PCR reactions (17, 18). The BRAF gene maps to chromosome 7, which is BRAF gene copy number was assessed by real-time qPCR using frequently gained, as a whole or in part, especially in BRAFmut the TaqMan technology on a Light-Cycler 480 instrument (Roche melanoma, contributing to variation of the amount of the Diagnostics). A 149 bp region was amplified with primers encom- mutant allele. Indeed, the percentage of the BRAFmut allele, passing the 600 codon in a multiplex reaction that also included although expected to be 50% as mutations in oncogenes are primers for albumin (ALB) as a reference gene, which appeared usually heterozygous, reportedly spans across a wide range of neither focally amplified nor deleted across a dataset of 3,131 values in melanoma samples (19–22). Because the BRAF V600 tumors that included 111 melanoma cases (data from http:// mutation is the target of BRAF inhibitors, the percentage of the www.broadinstitute.org/tumorscape; ref. 26). We used the rela- BRAFmut allele was suggested to influence the clinical efficacy tive quantification measured using the delta-Ct method with a of the treatment, but its association with patients' response is BRAF reference standard (Horizon Diagnostics) in each experi- still controversial (19, 23–25). ment and adjusted it according to the estimated tumor cell The aim of our study was to assess BRAF copy number and percentage. To validate our approach, we analyzed control DNA mutant allele frequency in pretherapy specimens from metastatic from FFPE normal skin samples that showed a BRAF/ALB ratio melanoma patients who received MAPKi and to investigate the ranging from 0.93 to 1.1 and denoting an equal copy number of correlation with patients' response to treatment. The identifica- the BRAF and ALB genes (range, 1.9–2.2 copies). The adenocar- tion of predictive biomarkers would allow the selection of cinoma cell line HT-29, for which chromosome 7 trisomy has patients who are most likely to benefit from MAPK-targeted been reported (27), was used as an additional control. HT-29 cells therapy, thus improving clinical management. were generously provided by Professor A. Rosato (University of Padua) after authentication by analyzing the short tandem Materials and Methods repeats profile by the GenePrint 10 System (Promega) and after negative Mycoplasma test by a MycoAlert kit (Lonza). Aliquotes of Patient cohort DNA extracted from these cells were used for this work. qPCR Fifty-one specimens (9 from primary tumors and 42 from analysis on HT-29 DNA showed a BRAF/ALB ratio of 1.5, as metastases) were collected, prior to MAPK-targeted therapy ini- expected. We therefore set a copy number of 2.3 as a cut-off to BRAF tiation, from 46 patients diagnosed with mut unresectable discriminate between a diploid BRAF status and BRAF gain. stage III or stage IV cutaneous melanoma, who were treated at the The quantification of the BRAFmut allele in each sample was – Veneto Institute of Oncology IOV IRCCS in Padua. Multiple obtained by ad hoc real-time PCR reactions set up to amplify the biopsies were available for 5 patients. V600E/K-mutated and wild-type (wt) alleles. The forward primer All patients received MAPK-targeted therapy: 34 (74%) were was mutation-specific, with a 30 terminus matching the V600E, treated with monotherapy [vemurafenib (22) or dabrafenib (12)] V600K, or the wt codon, whereas the reverse primer and the probe and 12 (26%) with
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