Research Papers:

Whole exome sequencing identifies a recurrent RQCD1 P131L mutation in cutaneous melanoma

Stephen Q. Wong _, Andreas Behren, Victoria J. Mar, Katherine Woods, Jason Li, Claire Martin, Karen E. Sheppard, Rory Wolfe, John Kelly, Jonathan Cebon, Alexander Dobrovic and Grant A. McArthur

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Oncotarget. 2015; 6:1115-1127. https://doi.org/10.18632/oncotarget.2747

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Stephen Q. Wong1, Andreas Behren2,3, Victoria J. Mar4,5, Katherine Woods2,3, Jason Li1, Claire Martin1, Karen E. Sheppard1,6, Rory Wolfe5, John Kelly4, Jonathan Cebon2,3, Alexander Dobrovic2,3,7, Grant A. McArthur1,7

1Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

2Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre Heidelberg, Victoria, Australia

3School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia

4Victorian Melanoma Service, Alfred Hospital, Prahran, Victoria, Australia

5Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Victoria, Australia

6Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia

7Department of Pathology, University of Melbourne, Parkville, Victoria, Australia

Correspondence to:

Stephen Q. Wong, e-mail: stephen.wong@petermac.org

Keywords: Melanoma, RQCD1, exome sequencing

Received: June 28, 2014     Accepted: November 11, 2014     Published: December 06, 2014


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.

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