Limits...
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.

Show MeSH

Related in: MedlinePlus

Mutational landscape of the CCR4-NOT complex genes in the TCGA databaseMutually exclusive pattern of CCR4-NOT complex gene members based on TCGA mutational data from the subcutaneous melanoma dataset (provisional). Each green rectangle represents the presence of at least one protein altering mutation. A grey rectangle indicates no mutations. The prevalence of a mutation in each gene is shown. Plot extracted from the cBioPortal for cancer genomics.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4359221&req=5

Figure 3: Mutational landscape of the CCR4-NOT complex genes in the TCGA databaseMutually exclusive pattern of CCR4-NOT complex gene members based on TCGA mutational data from the subcutaneous melanoma dataset (provisional). Each green rectangle represents the presence of at least one protein altering mutation. A grey rectangle indicates no mutations. The prevalence of a mutation in each gene is shown. Plot extracted from the cBioPortal for cancer genomics.

Mentions: Other genes that encode for members of the CCR4-NOT complex include CNOT1, CNOT2, CNOT3, CNOT4, CNOT6, CNOT6L, CNOT7, CNOT8, CNOT10 and CNOT11 [18]. Exploration of the mutational status of other members from the TCGA dataset (http://www.cbioportal.org) of subcutaneous melanoma revealed that genes were mutated in a mutually exclusive manner (Figure 3 and Supplementary Figure 1) with 21.2% of cases (n = 59) mutated in any one of the complex members. Six patients had the recurrent RQCD1 P131L mutation, with an additional three patients displaying S87P, N88Y or P131S mutations. All other genes in the CCR4-NOT complex that had mutations had no apparent hotspots.


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 the CCR4-NOT complex genes in the TCGA databaseMutually exclusive pattern of CCR4-NOT complex gene members based on TCGA mutational data from the subcutaneous melanoma dataset (provisional). Each green rectangle represents the presence of at least one protein altering mutation. A grey rectangle indicates no mutations. The prevalence of a mutation in each gene is shown. Plot extracted from the cBioPortal for cancer genomics.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Mutational landscape of the CCR4-NOT complex genes in the TCGA databaseMutually exclusive pattern of CCR4-NOT complex gene members based on TCGA mutational data from the subcutaneous melanoma dataset (provisional). Each green rectangle represents the presence of at least one protein altering mutation. A grey rectangle indicates no mutations. The prevalence of a mutation in each gene is shown. Plot extracted from the cBioPortal for cancer genomics.
Mentions: Other genes that encode for members of the CCR4-NOT complex include CNOT1, CNOT2, CNOT3, CNOT4, CNOT6, CNOT6L, CNOT7, CNOT8, CNOT10 and CNOT11 [18]. Exploration of the mutational status of other members from the TCGA dataset (http://www.cbioportal.org) of subcutaneous melanoma revealed that genes were mutated in a mutually exclusive manner (Figure 3 and Supplementary Figure 1) with 21.2% of cases (n = 59) mutated in any one of the complex members. Six patients had the recurrent RQCD1 P131L mutation, with an additional three patients displaying S87P, N88Y or P131S mutations. All other genes in the CCR4-NOT complex that had mutations had no apparent hotspots.

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