Disturbed protein–protein interaction networks in metastatic melanoma are associated with worse prognosis and increased functional mutation burden

Authors

  • Sarah-Jane Schramm,

    Corresponding author
    1. Melanoma Institute Australia, Sydney, NSW, Australia
    • Sydney Medical School, The University of Sydney at Westmead Millennium Institute for Medical Research, Sydney, NSW, Australia
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  • Simone S. Li,

    1. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
    2. Systems Biology Initiative, University of New South Wales, Sydney, NSW, Australia
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  • Vivek Jayaswal,

    1. School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia
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  • David C. Y. Fung,

    1. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
    2. Systems Biology Initiative, University of New South Wales, Sydney, NSW, Australia
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  • Anna E. Campain,

    1. School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia
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  • Chi N. I. Pang,

    1. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
    2. Systems Biology Initiative, University of New South Wales, Sydney, NSW, Australia
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  • Richard A. Scolyer,

    1. Melanoma Institute Australia, Sydney, NSW, Australia
    2. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
    3. Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
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  • Yee Hwa Yang,

    1. School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia
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  • Graham J. Mann,

    1. Sydney Medical School, The University of Sydney at Westmead Millennium Institute for Medical Research, Sydney, NSW, Australia
    2. Melanoma Institute Australia, Sydney, NSW, Australia
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  • Marc R. Wilkins

    1. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
    2. Systems Biology Initiative, University of New South Wales, Sydney, NSW, Australia
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CORRESPONDENCE Sarah-Jane Schramm, e-mail: graham.mann@sydney.edu.au

Summary

For disseminated melanoma, new prognostic biomarkers and therapeutic targets are urgently needed. The organization of protein–protein interaction networks was assessed via the transcriptomes of four independent studies of metastatic melanoma and related to clinical outcome and MAP-kinase pathway mutations (BRAF/NRAS). We also examined patient outcome-related differences in a predicted network of microRNAs and their targets. The 32 hub genes with the most reproducible survival-related disturbances in co-expression with their protein partner genes included oncogenes and tumor suppressors, previously known correlates of prognosis, and other proteins not previously associated with melanoma outcome. Notably, this network-based gene set could classify patients according to clinical outcomes with 67–80% accuracy among cohorts. Reproducibly disturbed networks were also more likely to have a higher functional mutation burden than would be expected by chance. The disturbed regions of networks are therefore markers of clinically relevant, selectable tumor evolution in melanoma which may carry driver mutations.

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