PMID- 28668077 OWN - NLM STAT- MEDLINE DCOM- 20180523 LR - 20231213 IS - 1471-5945 (Electronic) IS - 1471-5945 (Linking) VI - 17 IP - 1 DP - 2017 Jul 1 TI - Variation of mutant allele frequency in NRAS Q61 mutated melanomas. PG - 9 LID - 10.1186/s12895-017-0061-x [doi] LID - 9 AB - BACKGROUND: Somatic mutations of BRAF or NRAS activating the MAP kinase cell signaling pathway are present in 70% of cutaneous melanomas. The mutant allele frequency of BRAF V600E (M%BRAF) was recently shown to be highly heterogeneous in melanomas. The present study focuses on the NRAS Q61 mutant allele frequency (M%NRAS). METHODS: Retrospective quantitative analyze of 104 NRAS mutated melanomas was performed using pyrosequencing. Mechanisms of M%NRAS imbalance were studied by fluorescence in situ hybridization (FISH) and microsatellite analysis. RESULTS: M%NRAS was increased in 27.9% of cases. FISH revealed that chromosome 1 instability was the predominant mechanism of M%NRAS increase, with chromosome 1 polysomy observed in 28.6% of cases and intra-tumor cellular heterogeneity with copy number variations of chromosome 1/NRAS in 23.8%. Acquired copy-neutral loss of heterozygosity (LOH) was less frequent (19%). However, most samples with high M%NRAS had only one copy of NRAS locus surrounding regions suggesting a WT allele loss. Clinical characteristics and survival of patients with either <60% or >/=60% of M%NRAS were not different. CONCLUSION: As recently shown for M%BRAF, M%NRAS is highly heterogeneous. The clinical impacts of high M%NRAS should be investigated in a larger series of patients. FAU - Helias-Rodzewicz, Zofia AU - Helias-Rodzewicz Z AD - Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France. zofia.helias-ext@aphp.fr. AD - Department of Pathology, Ambroise Pare Hospital, AP-HP, Boulogne-Billancourt, France. zofia.helias-ext@aphp.fr. FAU - Funck-Brentano, Elisa AU - Funck-Brentano E AD - Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France. AD - Department of Dermatology, Ambroise Pare Hospital, AP-HP, Boulogne-Billancourt, France. FAU - Terrones, Nathalie AU - Terrones N AD - Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France. FAU - Beauchet, Alain AU - Beauchet A AD - Department of Public Health, Ambroise Pare Hospital Ap-HP, Boulogne-Billancourt, France. FAU - Zimmermann, Ute AU - Zimmermann U AD - Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France. AD - Department of Pathology, Ambroise Pare Hospital, AP-HP, Boulogne-Billancourt, France. FAU - Marin, Cristi AU - Marin C AD - Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France. AD - Department of Pathology, Ambroise Pare Hospital, AP-HP, Boulogne-Billancourt, France. FAU - Saiag, Philippe AU - Saiag P AD - Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France. AD - Department of Dermatology, Ambroise Pare Hospital, AP-HP, Boulogne-Billancourt, France. FAU - Emile, Jean-Francois AU - Emile JF AD - Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France. jean-francois.emile@uvsq.fr. AD - Department of Pathology, Ambroise Pare Hospital, AP-HP, Boulogne-Billancourt, France. jean-francois.emile@uvsq.fr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170701 PL - England TA - BMC Dermatol JT - BMC dermatology JID - 100968541 RN - 0 (Membrane Proteins) RN - EC 3.6.1.- (GTP Phosphohydrolases) RN - EC 3.6.1.- (NRAS protein, human) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Chromosome Aberrations MH - *Chromosomes, Human, Pair 1 MH - DNA Copy Number Variations MH - Female MH - GTP Phosphohydrolases/*genetics MH - *Gene Frequency MH - Humans MH - Kaplan-Meier Estimate MH - Male MH - Melanoma/*genetics/mortality MH - Membrane Proteins/*genetics MH - Middle Aged MH - *Mutation MH - Retrospective Studies MH - Skin Neoplasms/*genetics/mortality MH - Melanoma, Cutaneous Malignant PMC - PMC5494128 OTO - NOTNLM OT - Imbalance OT - M%NRAS OT - Melanoma OT - Pyrosequencing OT - WT allele loss COIS- ETHICAL APPROVAL AND CONSENT TO PARTICIPATE: The research was performed in compliance with the ethical principles of the Helsinki Declaration (1964) and with the French ethics laws. Patients were informed and approved the use of their samples for research purpose. Tumor samples collection was declared to the French Ministry of Research (DC 2009-933). Melan-Cohort study was approved by CPP IDF 8 Ethics committee (030209) and registered with https://www.clinicaltrials.gov/ct2/search (NCT00839410). CONSENT FOR PUBLICATION: Not applicable COMPETING INTERESTS: JF.E. received honoraria from Roche and Glaxo Smith Kline for counseling on patients with melanomas on the diagnosis and/or treatment with BRAF inhibitors. P.S. received honoraria for counseling on diagnosis and/or treatment of patients with melanomas from Roche and Glaxo Smith Kline. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2017/07/03 06:00 MHDA- 2018/05/24 06:00 PMCR- 2017/07/01 CRDT- 2017/07/03 06:00 PHST- 2017/01/30 00:00 [received] PHST- 2017/06/21 00:00 [accepted] PHST- 2017/07/03 06:00 [entrez] PHST- 2017/07/03 06:00 [pubmed] PHST- 2018/05/24 06:00 [medline] PHST- 2017/07/01 00:00 [pmc-release] AID - 10.1186/s12895-017-0061-x [pii] AID - 61 [pii] AID - 10.1186/s12895-017-0061-x [doi] PST - epublish SO - BMC Dermatol. 2017 Jul 1;17(1):9. doi: 10.1186/s12895-017-0061-x.