title: Increase in NRAS mutant allele percentage during metastatic melanoma progression.
abstract: One-fifth of cutaneous melanomas have dominant gain-of-function mutations of the NRAS oncogene. We report the first two cases of increasing NRAS mutant allele frequency in melanoma metastases and show that the chromosomal mechanism of this homozygosity is an increased polysomy of chromosome 1. We observed an increase in NRAS mutant allele percentage (NRAS-MA%) in the metastatic melanoma progression from 2 patients with melanomas harbouring a NRAS mutation (p.Q61K in case 1 and p.Q61R in case 2). In case 1, we observed a NRAS-MA% increase from 18% within the first metastatic node to 81%, 92% and 85% respectively in the three subsequent metastases: lymph node, brain and subcutaneous metastases biopsied 1, 6 and 17 months, respectively, after the initial lymph node biopsy. In case 2, we observed an increase in NRAS-MA% from 40% within the primary melanoma to 63% within the metastatic lymph node. FISH analysis showed the same results in both cases: a frequent polysomy of chromosome 1 in metastasis samples with NRAS mutant allele percentage >60%, while most cells were disomic in the samples with well-balanced heterozygous mutations. The percentage of NRAS mutant allele may increase during metastatic progression and may be associated with chromosomal instability. Further studies are needed to evaluate the prognostic impact of the NRAS homozygous status and/or polyploidy in metastatic cutaneous melanomas.
authors.affiliation: Research Unit EA 4340 'Biomarkers in cancerology and in hemato-oncology', Université de Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Boulogne-Billancourt, France.|Department of Dermatology, AP-HP Ambroise Paré Hospital, Boulogne-Billancourt, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Funck-Brentano
authors.affiliation: Research Unit EA 4340 'Biomarkers in cancerology and in hemato-oncology', Université de Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Boulogne-Billancourt, France.|Department of Pathology, AP-HP Ambroise Paré Hospital, Boulogne-Billancourt, France.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Hélias-Rodzewicz
authors.affiliation: Research Unit EA 4340 'Biomarkers in cancerology and in hemato-oncology', Université de Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Boulogne-Billancourt, France.|Department of Dermatology, AP-HP Ambroise Paré Hospital, Boulogne-Billancourt, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Longvert
authors.affiliation: Department of Neuropathology, AP-HP Pitié-Salpétrière Hospital, Paris, France.
authors.forename: Karima
authors.initials: K
authors.lastname: Mokhtari
authors.affiliation: Research Unit EA 4340 'Biomarkers in cancerology and in hemato-oncology', Université de Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Boulogne-Billancourt, France.|Department of Dermatology, AP-HP Ambroise Paré Hospital, Boulogne-Billancourt, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Saiag
authors.affiliation: Research Unit EA 4340 'Biomarkers in cancerology and in hemato-oncology', Université de Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Boulogne-Billancourt, France.|Department of Pathology, AP-HP Ambroise Paré Hospital, Boulogne-Billancourt, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
mesh_terms: D000368:Aged; D058674:Chromosome Duplication; D002878:Chromosomes, Human, Pair 1; D020558:GTP Phosphohydrolases / Q000235:genetics*; D000073659:Gain of Function Mutation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged
chemical_list: D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: NRAS melanoma; allelic imbalance; biomarker; homozygous mutation; polysomy