title: Molecular and genetic diversity in the metastatic process of melanoma.
abstract: Diversity between metastatic melanoma tumours in individual patients is known; however, the molecular and genetic differences remain unclear. To examine the molecular and genetic differences between metastatic tumours, we performed gene-expression profiling of 63 melanoma tumours obtained from 28 patients (two or three tumours/patient), followed by analysis of their mutational landscape, using targeted deep sequencing of 1697 cancer genes and DNA copy number analysis. Gene-expression signatures revealed discordant phenotypes between tumour lesions within a patient in 50% of the cases. In 18 of 22 patients (where matched normal tissue was available), we found that the multiple lesions within a patient were genetically divergent, with one or more melanoma tumours harbouring 'private' somatic mutations. In one case, the distant subcutaneous metastasis of one patient occurring 3 months after an earlier regional lymph node metastasis had acquired 37 new coding sequence mutations, including mutations in PTEN and CDH1. However, BRAF and NRAS mutations, when present in the first metastasis, were always preserved in subsequent metastases. The patterns of nucleotide substitutions found in this study indicate an influence of UV radiation but possibly also DNA alkylating agents. Our results clearly demonstrate that metastatic melanoma is a molecularly highly heterogeneous disease that continues to progress throughout its clinical course. The private aberrations observed on a background of shared aberrations within a patient provide evidence of continued evolution of individual tumours following divergence from a common parental clone, and might have implications for personalized medicine strategies in melanoma treatment.
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Sweden; CREATE Health Strategic Centre for Clinical Cancer Research, Lund University, Sweden.
authors.forename: Katja
authors.initials: K
authors.lastname: Harbst
authors.forename: Martin
authors.initials: M
authors.lastname: Lauss
authors.forename: Helena
authors.initials: H
authors.lastname: Cirenajwis
authors.forename: Christof
authors.initials: C
authors.lastname: Winter
authors.forename: Jillian
authors.initials: J
authors.lastname: Howlin
authors.forename: Therese
authors.initials: T
authors.lastname: Törngren
authors.forename: Anders
authors.initials: A
authors.lastname: Kvist
authors.forename: Björn
authors.initials: B
authors.lastname: Nodin
authors.forename: Eleonor
authors.initials: E
authors.lastname: Olsson
authors.forename: Jari
authors.initials: J
authors.lastname: Häkkinen
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.forename: Lotta
authors.initials: L
authors.lastname: Lundgren
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.forename: Christian
authors.initials: C
authors.lastname: Ingvar
authors.forename: Sofia K
authors.initials: SK
authors.lastname: Gruvberger-Saal
authors.forename: Lao H
authors.initials: LH
authors.lastname: Saal
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000235:genetics*; D015820:Cadherins / Q000235:genetics; D002877:Chromosomes, Human; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis / Q000379:methods; D018450:Disease Progression; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D059467:Transcriptome
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: BRAF; NRAS; deep sequencing; gene expression; melanoma