Journal
ONCOTARGET
Volume 6, Issue 2, Pages 1115-1127Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2747
Keywords
Melanoma; RQCD1; exome sequencing
Categories
Funding
- Victorian Government through the Victorian Cancer Agency Translational Research Program Grant [EOI09/27]
- National Health and Medical Research Council of Australia (NHMRC) [1053792, 1002698, 1042980, 1042986, 1002654]
- NHMRC [1042986]
- Victorian State Government Operational Infrastructure Support Program
- Cure Cancer Australia Foundation Fellowship
- Melanoma Research Alliance (MRA)
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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 similar to 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 similar to 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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