title: Clinical and pathological associations of the activating RAC1 P29S mutation in primary cutaneous melanoma.
abstract: Activating mutations in the GTPase RAC1 are a recurrent event in cutaneous melanoma. We investigated the clinical and pathological associations of RAC1(P29S) in a cohort of 814 primary cutaneous melanomas with known BRAF and NRAS mutation status. The RAC1(P29S) mutation had a prevalence of 3.3% and was associated with increased thickness (OR=1.6 P = 0.001), increased mitotic rate (OR=1.3 P = 0.03), ulceration (OR=2.4 P = 0.04), nodular subtype (OR=3.4 P = 0.004), and nodal disease at diagnosis (OR=3.3 P = 0.006). BRAF mutant tumors were also associated with nodal metastases (OR=1.9 P = 0.004), despite being thinner at diagnosis than BRAF WT (median 1.2 mm versus 1.6 mm, P < 0.001). Immunohistochemical analysis of 51 melanomas revealed that 47% were immunoreactive for RAC1. Melanomas were more likely to show RAC1 immunoreactivity if they were BRAF mutant (OR=5.2 P = 0.01). RAC1 may therefore be important in regulating the early migration of BRAF mutant tumors. RAC1 mutations are infrequent in primary melanomas but may accelerate disease progression.
authors.affiliation: Victorian Melanoma Service, Alfred Hospital, Melbourne, Vic., Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic., Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Mar
authors.forename: Stephen Q
authors.initials: SQ
authors.lastname: Wong
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Logan
authors.forename: Trung
authors.initials: T
authors.lastname: Nguyen
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
authors.forename: John W
authors.initials: JW
authors.lastname: Kelly
authors.forename: Rory
authors.initials: R
authors.lastname: Wolfe
authors.forename: Alexander
authors.initials: A
authors.lastname: Dobrovic
authors.forename: Catriona
authors.initials: C
authors.lastname: McLean
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D014466:Ultraviolet Rays; D020830:rac1 GTP-Binding Protein / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C107953:RAC1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D020830:rac1 GTP-Binding Protein
keywords: BRAF; RAC1 expression; RAC1 immunoreactivity; RAC1 mutation; melanoma metastasis; melanoma progression