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Title: Whole exome sequencing identifies a recurrent RQCD1 P131L mutation in cutaneous melanoma.
Austin Authors: Wong, Stephen Q;Behren, Andreas;Mar, Victoria J;Woods, Katherine;Li, Jason;Sheppard, Karen E;Wolfe, Rory;Kelly, John;Cebon, Jonathan S ;Dobrovic, Alexander ;McArthur, Grant A
Affiliation: Victorian Melanoma Service, Alfred Hospital, Prahran, Victoria, Australia
Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Victoria, Australia
Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre Heidelberg, Victoria, Australia
Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
Issue Date: 20-Jan-2015
Publication information: Oncotarget; 6(2): 1115-27
Abstract: Melanoma is often caused by mutations due to exposure to ultraviolet radiation. This study reports a recurrent somatic C > T change causing a P131L mutation in the RQCD1 (Required for Cell Differentiation1 Homolog) gene identified through whole exome sequencing of 20 metastatic melanomas. Screening in 715 additional primary melanomas revealed a prevalence of ~4%. This represents the first reported recurrent mutation in a member of the CCR4-NOT complex in cancer. Compared to tumors without the mutation, the P131L mutant positive tumors were associated with increased thickness (p = 0.02), head and neck (p = 0.009) and upper limb (p = 0.03) location, lentigo maligna melanoma subtype (p = 0.02) and BRAF V600K (p = 0.04) but not V600E or NRAS codon 61 mutations. There was no association with nodal disease (p = 0.3). Mutually exclusive mutations of other members of the CCR4-NOT complex were found in ~20% of the TCGA melanoma dataset suggesting the complex may play an important role in melanoma biology. Mutant RQCD1 was predicted to bind strongly to HLA-A0201 and HLA-Cw3 MHC1 complexes. From thirteen patients with mutant RQCD1, an anti-tumor CD8⁺ T cell response was observed from a single patient's peripheral blood mononuclear cell population stimulated with mutated peptide compared to wildtype indicating a neoantigen may be formed.
Gov't Doc #: 25544760
Type: Journal Article
Appears in Collections:Journal articles

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