The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Åke Borg

Åke Borg

Principal investigator

Åke Borg

Gene Expression Profiling-Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome.

Author

  • Göran B Jönsson
  • Christian Busch
  • Stian Knappskog
  • Jürgen Geisler
  • Hrvoje Miletic
  • Markus Ringnér
  • Johan R Lillehaug
  • Åke Borg
  • Per Eystein Lonning

Summary, in English

PURPOSE: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. While spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers selecting patients for immune therapy. Experimental design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus and NRAS/BRAF mutation screening. RESULTS: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation or stromal composition genes. Even though all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (p<0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by high frequency of CDKN2A homozygous deletions (p<0.01). We observed different prognosis between the subtypes (p=0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared to the others (p = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III/IV melanomas. Moreover, low expression of an a priori-defined gene set associated to immune response signaling was significantly associated to poor outcome (p=0.001). CONCLUSIONS: Our data reveal a biologically-based taxonomy of malignant melanomas with prognostic impact and support an influence of the anti-tumoral immune response on outcome.

Department/s

  • Breastcancer-genetics
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year

2010

Language

English

Pages

3356-3367

Publication/Series

Clinical Cancer Research

Volume

16

Issue

13

Document type

Journal article

Publisher

American Association for Cancer Research

Topic

  • Cancer and Oncology

Status

Published

ISBN/ISSN/Other

  • ISSN: 1078-0432