Somatic Mutations in MAP3K5 Attenuate Its Proapoptotic Function in Melanoma through Increased Binding to Thioredoxin

Prickett, Todd D.; Zerlanko, Brad J.; Gartner, Jared J.; Parker, Stephen C. J.; Dutton‐Regester, Ken; Lin, Jimmy C.; Teer, Jamie K.; Wei, Xiaomu; Jiang, Jiji; Chen, Guoyong; Davies, Michael A.; Gershenwald, Jeffrey E.; Robinson, William A.; Robinson, Steven E.; Hayward, Nicholas K.; Rosenberg, Steven A.; Margulies, Elliott H.; Samuels, Yardena

doi:10.1038/jid.2013.365

Cited by 21 publications

(14 citation statements)

References 43 publications

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“…Inactivation mutations in ARID2, which encodes a component of the SWI/SNF chromatin remodeling complex, are observed in melanoma [23], and the nonsense ARID Q1165* mutation was enriched in the ctDNA of patient 8 (Table S5). The MAP3K5 R256C mutation identified in ctDNA and melanoma gDNA from patient 10 has also been identified in melanoma, and shown to inhibit the pro-death activity of this kinase [30].…”

Section: Other Highlighted Mutationsmentioning

confidence: 90%

Analysis of the Whole-Exome Sequencing of Tumor and Circulating Tumor DNA in Metastatic Melanoma

Diefenbach

Lee

Strbenac

et al. 2019

Cancers

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The use of circulating tumor DNA (ctDNA) to monitor cancer progression and response to therapy has significant potential but there is only limited data on whether this technique can detect the presence of low frequency subclones that may ultimately confer therapy resistance. In this study, we sought to evaluate whether whole-exome sequencing (WES) of ctDNA could accurately profile the mutation landscape of metastatic melanoma. We used WES to identify variants in matched, tumor-derived genomic DNA (gDNA) and plasma-derived ctDNA isolated from a cohort of 10 metastatic cutaneous melanoma patients. WES parameters such as sequencing coverage and total sequencing reads were comparable between gDNA and ctDNA. The mutant allele frequency of common single nucleotide variants was lower in ctDNA, reflecting the lower read depth and minor fraction of ctDNA within the total circulating free DNA pool. There was also variable concordance between gDNA and ctDNA based on the total number and identity of detected variants and this was independent of the tumor biopsy site. Nevertheless, established melanoma driver mutations and several other melanoma-associated mutations were concordant between matched gDNA and ctDNA. This study highlights that WES of ctDNA could capture clinically relevant mutations present in melanoma metastases and that enhanced sequencing sensitivity will be required to identify low frequency mutations.

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Section: Other Highlighted Mutationsmentioning

confidence: 90%

Analysis of the Whole-Exome Sequencing of Tumor and Circulating Tumor DNA in Metastatic Melanoma

Diefenbach

Lee

Strbenac

et al. 2019

Cancers

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“…For example, SF3B1 mutations are frequently found in mucosal and ocular melanoma [ 7 , 8 , 9 ]. Mutations in TERT , CDKN2A , NF1 , and RAC1 are often mutated in cutaneous melanomas, and recurrent variants in NFKBIE are found in desmoplastic melanoma [ 7 , 10 ]. However, these studies often lack the clinical knowledge of patient outcomes such as treatment response, and thus do not address how the genomic variants delineates responsiveness to immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy

Amato

Hintzsche

Wells

et al. 2020

Cancers

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Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma. However, predicting which patients will respond to immunotherapy remains a significant knowledge gap. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response based on RECIST 1.1 criteria. The responders group contained 21 patients that had a complete or partial response, while the 31 non-responders had stable or progressive disease. Whole exome sequencing (WES) was used to identify biomarkers of anti-PD1 response from somatic mutations between the two groups. Variants in codons G34 and G41 in NFKBIE, a negative regulator of NFkB, were found exclusively in the responders. Mutations in NKBIE-related genes were also enriched in the responder group compared to the non-responders. Patients that harbored NFKBIE-related gene mutations also had a higher mutational burden, decreased tumor volume with treatment, and increased progression-free survival. RNA sequencing on a subset of tumor samples identified that CD83 was highly expressed in our responder group. Additionally, Gene Set Enrichment Analysis showed that the TNFalpha signaling via NFkB pathway was one of the top pathways with differential expression in responders vs. non-responders. In vitro NFkB activity assays indicated that the G34E variant caused loss-of-function of NFKBIE, and resulted in activation of NFkB signaling. Flow cytometry assays indicated that G34E variant was associated with upregulation of CD83 in human melanoma cell lines. These results suggest that NFkB activation and signaling in tumor cells contributes to a favorable anti-PD1 treatment response, and clinical screening to include aberrations in NFkB-related genes should be considered.

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“…Once activated, MAP3K5 can trigger the apoptogenic kinase cascade via activation of C-Jun N-terminal kinase and p38-MAP kinase, resulting in apoptosis and delayed gastric emptying (Kanamoto et al, 2000;Tobiume et al, 2001;Yang et al, 2014). MAP3K5 also plays an important role in oxidative stress, cellular proliferation, and differentiation, and in immune responses (Harada et al, 2006;Hayakawa et al, 2006;Choi et al, 2011;Prickett et al, 2014). Residual feed intake (RFI) is closely associated with tissue growth, apoptosis, differentiation, gastric emptying rate, and immune responses (De Hear et al, 1993;Kim et al, 2007;Smith et al, 2011;Dunkelberger et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Porcine MAP3K5 analysis: molecular cloning, characterization, tissue expression pattern, and copy number variations associated with residual feed intake

Zhang

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Mitogen-activated protein kinase kinase kinase 5 (MAP3K5) is essential for apoptosis, proliferation, differentiation, and immune responses, and is a candidate marker for residual feed intake (RFI) in pig. We cloned the full-length cDNA sequence of porcine MAP3K5 by rapid-amplification of cDNA ends. The 5451-bp gene contains a 5'-untranslated region (UTR) (718 bp), a coding region (3738 bp), and a 3'-UTR (995 bp), and encodes a peptide of 1245 amino acids, which shares 97, 99, 97, 93, 91, and 84% sequence identity with cattle, sheep, human, mouse, chicken, and zebrafish MAP3K5, respectively. The deduced MAP3K5 protein sequence contains two conserved domains: a DUF4071 domain and a protein kinase domain. Phylogenetic analysis showed that porcine MAP3K5 forms a separate branch to vicugna and camel MAP3K5. Tissue expression analysis using real-time quantitative polymerase chain reaction (qRT-PCR) revealed that MAP3K5 was expressed in the heart, liver, spleen, lung, kidney, muscle, fat, pancrea, ileum, and stomach tissues. Copy number variation was detected for porcine MAP3K5 and validated by qRT-PCR. Furthermore, a significant increase in average copy number was detected in the low RFI group when compared to the high RFI group in a Duroc pig population. These results provide useful information regarding the influence of MAP3K5 on RFI in pigs.

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Somatic Mutations in MAP3K5 Attenuate Its Proapoptotic Function in Melanoma through Increased Binding to Thioredoxin

Cited by 21 publications

References 43 publications

Analysis of the Whole-Exome Sequencing of Tumor and Circulating Tumor DNA in Metastatic Melanoma

Analysis of the Whole-Exome Sequencing of Tumor and Circulating Tumor DNA in Metastatic Melanoma

Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy

Porcine MAP3K5 analysis: molecular cloning, characterization, tissue expression pattern, and copy number variations associated with residual feed intake

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