title: Disturbed protein-protein interaction networks in metastatic melanoma are associated with worse prognosis and increased functional mutation burden.
abstract: 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.
authors.affiliation: Sydney Medical School, The University of Sydney at Westmead Millennium Institute for Medical Research, Sydney, NSW, Australia.
authors.forename: Sarah-Jane
authors.initials: SJ
authors.lastname: Schramm
authors.forename: Simone S
authors.initials: SS
authors.lastname: Li
authors.forename: Vivek
authors.initials: V
authors.lastname: Jayaswal
authors.forename: David C Y
authors.initials: DC
authors.lastname: Fung
authors.forename: Anna E
authors.initials: AE
authors.lastname: Campain
authors.forename: Chi N I
authors.initials: CN
authors.lastname: Pang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Yee Hwa
authors.initials: YH
authors.lastname: Yang
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: Marc R
authors.initials: MR
authors.lastname: Wilkins
mesh_terms: D017281:Cost of Illness; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding / Q000235:genetics; D060066:Protein Interaction Maps; D015203:Reproducibility of Results; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D035683:MicroRNAs; D009363:Neoplasm Proteins
keywords: cancer systems biology; gene expression microarray; melanoma; melanoma prognosis; microRNA; protein-protein interaction