title: BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene profile predict poor outcome in patients with stage III melanoma.
abstract: Prediction of outcome for melanoma patients with surgically resected macroscopic nodal metastases is very imprecise. We performed a comprehensive clinico-pathologic assessment of fresh-frozen macroscopic nodal metastases and the preceding primary melanoma, somatic mutation profiling, and gene expression profiling to identify determinants of outcome in 79 melanoma patients. In addition to disease stage <II at initial presentation, the following clinical and pathologic factors were independent predictors of improved outcome (odds ratios for survival >4 years, 90% confidence interval): the presence of a nodular component in the primary melanoma (6.8, 0.6-76.0), and small cell size (11.1, 0.8-100.0) or low pigmentation (3.0, 0.8-100.0) in the nodal metastases. Absence of BRAF mutation (20.0, 1.0-1000.0) or NRAS mutation (16.7, 0.6-1000.0) were both favorable prognostic factors. A 46-gene expression signature with strong overrepresentation of immune response genes was predictive of better survival (10.9, 0.4-325.6); in the full cohort, median survival was >100 months in those with the signature, but 10 months in those without. This relationship was validated in two previously published independent stage III melanoma data sets. We conclude that the presence of BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene profile predict poor outcome in melanoma patients with macroscopic stage III disease.
authors.affiliation: The University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: Gulietta M
authors.initials: GM
authors.lastname: Pupo
authors.forename: Anna E
authors.initials: AE
authors.lastname: Campain
authors.forename: Candace D
authors.initials: CD
authors.lastname: Carter
authors.forename: Sarah-Jane
authors.initials: SJ
authors.lastname: Schramm
authors.forename: Svetlana
authors.initials: S
authors.lastname: Pianova
authors.forename: Sebastien K
authors.initials: SK
authors.lastname: Gerega
authors.forename: Chitra
authors.initials: C
authors.lastname: De Silva
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lai
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.forename: Maria
authors.initials: M
authors.lastname: Synnott
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Yee Hwa
authors.initials: YH
authors.lastname: Yang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
mesh_terms: D016208:Databases, Factual / Q000706:statistics & numerical data; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods / Q000592:standards; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000401:mortality* / Q000556:secondary / Q000601:surgery; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015203:Reproducibility of Results; D012878:Skin Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D059467:Transcriptome / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf