title: Molecular stratification of metastatic melanoma using gene expression profiling: Prediction of survival outcome and benefit from molecular targeted therapy.
abstract: Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Cirenajwis
authors.affiliation: Department of Clinical Sciences, Division of Surgery, Lund University, Lund, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekedahl
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Lauss
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Katja
authors.initials: K
authors.lastname: Harbst
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.|Department of Oncology, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Ana
authors.initials: A
authors.lastname: Carneiro
authors.affiliation: Department of Clinical Pathology, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Enoksson
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Frida
authors.initials: F
authors.lastname: Rosengren
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Werner-Hartman
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Törngren
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Kvist
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Fredlund
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.affiliation: Department of Clinical Pathology, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.|Department of Oncology, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Lotta
authors.initials: L
authors.lastname: Lundgren
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Jillian
authors.initials: J
authors.lastname: Howlin
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Sofia K
authors.initials: SK
authors.lastname: Gruvberger-Saal
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Lao H
authors.initials: LH
authors.lastname: Saal
authors.affiliation: Department of Dermatology, Helsingborg General Hospital, Helsingborg, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Nielsen
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Ringnér
authors.affiliation: Department of Dermatology, Harvard Medical School, Boston, USA.|Wellman Center for Photomedicine, MGH Cancer Center, Massachusetts General Hospital, Boston, USA.
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.|Department of Oncology, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.affiliation: Department of Clinical Sciences, Division of Surgery, Lund University, Lund, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Ingvar
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000627:therapeutic use; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines
keywords: BRAF; BRAF inhibitor; gene expression; melanoma; mutation