title: Whole exome sequencing identifies a recurrent RQCD1 P131L mutation in cutaneous melanoma.
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.
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Stephen Q
authors.initials: SQ
authors.lastname: Wong
authors.affiliation: Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre Heidelberg, Victoria, Australia.|School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Behren
authors.affiliation: Victorian Melanoma Service, Alfred Hospital, Prahran, Victoria, Australia.|Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Victoria, Australia.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Mar
authors.affiliation: Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre Heidelberg, Victoria, Australia.|School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Woods
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Martin
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.|Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Sheppard
authors.affiliation: Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Victoria, Australia.
authors.forename: Rory
authors.initials: R
authors.lastname: Wolfe
authors.affiliation: Victorian Melanoma Service, Alfred Hospital, Prahran, Victoria, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Kelly
authors.affiliation: Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre Heidelberg, Victoria, Australia.|School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
authors.affiliation: Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre Heidelberg, Victoria, Australia.|School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.|Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dobrovic
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D059472:Exome / Q000235:genetics*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D016015:Logistic Models; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D017386:Sequence Homology, Amino Acid; D012878:Skin Neoplasms; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D000096142:Cutaneous Malignant Melanoma
chemical_list: C468527:CNOT9 protein, human; D006680:HLA Antigens; D008565:Membrane Proteins; D014157:Transcription Factors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human