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.
Highlights
Melanoma is an aggressive form of skin cancer, with mutations in BRAF and NRAS genes occurring in ~50% and ~15% of tumors respectively
To identify novel driver genes in melanoma, we screened for somatic mutations in 20 metastatic melanoma cell lines and paired matched blood DNA using exome sequencing [13]
While there was a trend for BRAF/NRAS wildtype tumors to be associated with high mutation loads, this did not reach statistical significance because of the small number of cases in this cohort (p = 0.14)
Summary
Melanoma is an aggressive form of skin cancer, with mutations in BRAF and NRAS genes occurring in ~50% and ~15% of tumors respectively. Exposure to ultraviolet (UV) radiation induces C > T nucleotide changes at dipyrimidine sites which are responsible for high mutation rates observed in melanomas [1], those wildtype for both BRAF and NRAS [2]. Whilst most UV induced mutations are likely to be passenger events, others have been suggested to be involved in tumor development such as the activating RAC1 P29S mutation that occurs in approximately 5% of melanoma cases [1, 6, 7]. Those associated with UV damage are still yet to be discovered
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