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

Wong SQ, Behren A, Mar VJ, Woods K, Li J, Martin C, Sheppard KE, Wolfe R, Kelly J, Cebon J, Dobrovic A, McArthur GA - Oncotarget (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.

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.

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Mutational landscape of 20 metastatic melanomasGenetic landscape of 20 metastatic melanoma cell lines from the Ludwig institute and RQCD1 P131L mutant melanomas from the TCGA dataset. Numbers of somatic non-synonymous mutations across matched melanoma samples are shown in the top bar graph with the type of nucleotide change indicated in the legend (Not shown for TCGA dataset). The mutational status of samples is indicated for classical melanoma genes including BRAF, NRAS, NF1, PREX2, MAP2K1 and PTEN with a light blue coloured rectangle indicating the presence of at least one mutation in the gene. Only mutations in exon 15 of BRAF, exon 3 of NRAS, and the RQCD1 P131L are shown. For BRAF, V600E, V600K are represented by a dark blue or green rectangle, respectively.
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Figure 1: Mutational landscape of 20 metastatic melanomasGenetic landscape of 20 metastatic melanoma cell lines from the Ludwig institute and RQCD1 P131L mutant melanomas from the TCGA dataset. Numbers of somatic non-synonymous mutations across matched melanoma samples are shown in the top bar graph with the type of nucleotide change indicated in the legend (Not shown for TCGA dataset). The mutational status of samples is indicated for classical melanoma genes including BRAF, NRAS, NF1, PREX2, MAP2K1 and PTEN with a light blue coloured rectangle indicating the presence of at least one mutation in the gene. Only mutations in exon 15 of BRAF, exon 3 of NRAS, and the RQCD1 P131L are shown. For BRAF, V600E, V600K are represented by a dark blue or green rectangle, respectively.

Mentions: There were a total of 68,450 exomic somatic mutations in this dataset, with the average tumor displaying 3,422 (range from 269–26,493) somatic mutations. Consistent with UV damage, the tumors displayed a disproportionate level of C > T/G > A mutations which on average, accounted for 81% of all nucleotide changes (Figure 1). Recurrent non-synonymous mutations, including BRAF V600E (n = 8)/V600K (n = 4) were found as well as codon 61 mutations in NRAS (n = 4). Not unexpectedly, low mutation rates were associated with positive BRAF (p = 0.006) and NRAS mutation status (p = 0.04). 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).


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

Wong SQ, Behren A, Mar VJ, Woods K, Li J, Martin C, Sheppard KE, Wolfe R, Kelly J, Cebon J, Dobrovic A, McArthur GA - Oncotarget (2015)

Mutational landscape of 20 metastatic melanomasGenetic landscape of 20 metastatic melanoma cell lines from the Ludwig institute and RQCD1 P131L mutant melanomas from the TCGA dataset. Numbers of somatic non-synonymous mutations across matched melanoma samples are shown in the top bar graph with the type of nucleotide change indicated in the legend (Not shown for TCGA dataset). The mutational status of samples is indicated for classical melanoma genes including BRAF, NRAS, NF1, PREX2, MAP2K1 and PTEN with a light blue coloured rectangle indicating the presence of at least one mutation in the gene. Only mutations in exon 15 of BRAF, exon 3 of NRAS, and the RQCD1 P131L are shown. For BRAF, V600E, V600K are represented by a dark blue or green rectangle, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359221&req=5

Figure 1: Mutational landscape of 20 metastatic melanomasGenetic landscape of 20 metastatic melanoma cell lines from the Ludwig institute and RQCD1 P131L mutant melanomas from the TCGA dataset. Numbers of somatic non-synonymous mutations across matched melanoma samples are shown in the top bar graph with the type of nucleotide change indicated in the legend (Not shown for TCGA dataset). The mutational status of samples is indicated for classical melanoma genes including BRAF, NRAS, NF1, PREX2, MAP2K1 and PTEN with a light blue coloured rectangle indicating the presence of at least one mutation in the gene. Only mutations in exon 15 of BRAF, exon 3 of NRAS, and the RQCD1 P131L are shown. For BRAF, V600E, V600K are represented by a dark blue or green rectangle, respectively.
Mentions: There were a total of 68,450 exomic somatic mutations in this dataset, with the average tumor displaying 3,422 (range from 269–26,493) somatic mutations. Consistent with UV damage, the tumors displayed a disproportionate level of C > T/G > A mutations which on average, accounted for 81% of all nucleotide changes (Figure 1). Recurrent non-synonymous mutations, including BRAF V600E (n = 8)/V600K (n = 4) were found as well as codon 61 mutations in NRAS (n = 4). Not unexpectedly, low mutation rates were associated with positive BRAF (p = 0.006) and NRAS mutation status (p = 0.04). 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).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.

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.

Show MeSH
Related in: MedlinePlus