Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing

Stark, Mitchell; Woods, Susan L.; Gartside, Michael G.; Bonazzi, Vanessa; Dutton‐Regester, Ken; Aoude, Lauren G.; Chow, Donald; Sereduk, Chris; Niemi, Natalie M.; Tang, Nanyun; Ellis, Jonathan; Reid, Jeffrey G.; Zismann, Victoria; Tyagi, Sonika; Muzny, Donna M.; Newsham, Irene; Wu, Yuanqing; Palmer, Jane M.; Pollak, Thomas; Youngkin, David; Brooks, Bradford; Lanagan, Catherine; Schmidt, Chris; Kobe, Boštjan; MacKeigan, Jeffrey P.; Yin, Hongwei; Brown, Kevin M.; Gibbs, Richard A.; Trent, Jeffrey M.; Hayward, Nicholas K.

doi:10.1038/ng.1041

Cited by 173 publications

(176 citation statements)

References 43 publications

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“…This kinase is an upstream activator of the JNK and ERK pathways (29,30). The role of MAP3K9 in cancer is not well defined, but mutations in this kinase were recently found in 15% of patients with metastatic melanoma (29). We performed a deconvolution experiment and observed that three of four siRNA oligos were specific for MAP3K9 and significantly decreased proliferation (P < 0.005; Fig.…”

Section: Gof Mutation In Map3k9 Leads To Preferential Activation Of Tmentioning

confidence: 93%

“…MAP3K9 is a member of the mixed lineage family of kinases and is composed of an SH3 domain, Ser/Thr kinase domain, and a Cdc42/Rac interactive binding (CRIB) domain (28). This kinase is an upstream activator of the JNK and ERK pathways (29,30). The role of MAP3K9 in cancer is not well defined, but mutations in this kinase were recently found in 15% of patients with metastatic melanoma (29).…”

Section: Gof Mutation In Map3k9 Leads To Preferential Activation Of Tmentioning

confidence: 99%

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Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer

Fawdar¹,

Trotter²,

Li³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Approximately 70% of patients with non-small-cell lung cancer present with late-stage disease and have limited treatment options, so there is a pressing need to develop efficacious targeted therapies for these patients. This remains a major challenge as the underlying genetic causes of ∼50% of non-small-cell lung cancers remain unknown. Here we demonstrate that a targeted genetic dependency screen is an efficient approach to identify somatic cancer alterations that are functionally important. By using this approach, we have identified three kinases with gain-of-function mutations in lung cancer, namely FGFR4, MAP3K9, and PAK5. Mutations in these kinases are activating toward the ERK pathway, and targeted depletion of the mutated kinases inhibits proliferation, suppresses constitutive activation of downstream signaling pathways, and results in specific killing of the lung cancer cells. Genomic profiling of patients with lung cancer is ushering in an era of personalized medicine; however, lack of actionable mutations presents a significant hurdle. Our study indicates that targeted genetic dependency screens will be an effective strategy to elucidate somatic variants that are essential for lung cancer cell viability.driver mutations | MAPK pathway | signal transduction | siRNA screen

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Section: Gof Mutation In Map3k9 Leads To Preferential Activation Of Tmentioning

confidence: 93%

Section: Gof Mutation In Map3k9 Leads To Preferential Activation Of Tmentioning

confidence: 99%

Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer

Fawdar¹,

Trotter²,

Li³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…4 Besides recurrent mutations in TERT promoter, BRAF/NRAS, CDKN2A, NF1, PTEN and others genes, various sequencing initiatives have identified mutations in a number of other genes including GRIN2A, RAC1, BCL2L12, STK19, FBXW7 and RPS27. [5][6][7][8][9][10][11][12][13][14] The mutations in the promoter of TERT gene, mainly at 2124 (Chr 5:1,295,228 hg19 coordinate) and 2146 bp (1,295,250) positions from ATG site, enhance TERT expression through creation of binding motifs for Ets transcription factors. 15 The promoter mutations, similar to BRAF mutations, have emerged as the most frequent somatic alterations in melanoma.…”

mentioning

confidence: 99%

TERT promoter mutations in melanoma survival

Nagore

Heidenreich

Rachakonda

et al. 2016

Intl Journal of Cancer

102

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Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter.Cutaneous melanoma represents one of the most aggressive skin cancers with its propensity to metastasize and intrinsic resistance to treatment. 1 A majority of melanomas remain localized; however, in a proportion of patients, the tumors metastasize to local and distant organs with dismal outcomes.The refractoriness to treatment of patients with metastasized melanoma has been the main cause of the deaths associated with the disease. 2 Despite increased possibilities, with range of treatments including targeted and immunotherapies, of eliciting stable responses in patients with metastatic melanoma, the long-term prospectus in terms of treatment response is confined to disease management. 3 The identification of patients at risk of developing advanced disease at an early stage through use of somatic mutations as molecular biomarkers remains a valid medical issue.The melanoma genome is characterized by one of the highest prevalence of somatic mutations, and the mutational pattern depicts characteristic ultraviolet signature. 4 Besides recurrent mutations in TERT promoter, BRAF/NRAS, CDKN2A, NF1, PTEN and others genes, various sequencing initiatives have identified mutations in a number of other genes including GRIN2A, RAC1, BCL2L12, STK19, FBXW7 and RPS27. [5][6][7][8][9][10][11][12][13][14] The mutations in the promoter of TERT gene, mainly at 2124 (...

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“…Novel genetic mutations associated with tumorigenesis, tumor progression and metastasis have been identified using NGS, including those in genes encoding isocitrate dehydrogenase 1 (IDH1) in glioblastoma multiforme (8) and acute myeloid leukemia (9), chromodomain helicase DNA-binding protein 7 in small cell lung cancers (10), glutamate metabotropic receptor 3, transformation/transcription domain-associated protein, mitogen-activated protein kinase kinase 1/2, mitogen-activated protein kinase kinase kinase 5/9 and phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchange factor 2 in melanoma (11)(12)(13)(14)(15), Notch homolog 1 (NOTCH1) in chronic lymphocytic leukemia (16), splicing factor 3B subunit 1 in myelodysplasia (17,18), and chromatin-remodeling proteins such as AT-rich-interaction domain 1A in ovarian, kidney and gastric cancer (19,20). Historically, the discovery of somatic mutations in various types of cancer has been unexpected due to conventional methods based on direct sequencing.…”

Section: Introductionmentioning

confidence: 99%

Targeted sequencing of cancer‑associated genes in hepatocellular carcinoma using next‑generation sequencing

et al. 2017

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Abstract. Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Although the clinical success rate for the treatment of early-stage HCC has improved, the prognosis of advanced HCC remains poor owing to the high recurrence rate and the refractory nature of HCC for various anticancer drugs. A better understanding of the pathogenesis of HCC is therefore critically needed in order to treat HCC, including its genetic alterations. Next-generation sequencing (NGS) has provided an unbiased platform to systematically identify gene mutations and reveal the pathogenesis of various cancers. In the present study, a total of 118 samples (59 liver tissues including cancer and adjacent normal tissues) were sequenced using the AmpliSeq Hotspot Cancer Panel (version 2). The most common somatic mutations identified were tumor protein 53 (TP53; 35.6%) and β-catenin 1 (CTNNB1; 30.5%), and the most frequent variants of those genes were missense variants. In addition, somatic mutations including those in genes encoding colony-stimulating factor 1 receptor (5.1%), epidermal growth factor receptor (6.8%), RET proto-oncogene (3.4%), Erb-B2 receptor tyrosine kinase 4 (ERBB4; 1.7%) and serine/threonine kinase 11 (STK11, also known as liver kinase B1; 6.8%) were also identified at a low frequency in patients with HCC. A frameshift variant in STK11, a splice acceptor variant in TP53, a splice region variant in ERBB4 and a stop-gained variant in TP53 were also specifically determined. The most abundant alteration was a C:G>T:A transition (50%) and other transversions, i.e., C:G>G:C (19.6%), T:A>C:G (19.6%), C:G>A:T (12.5%), T:A>G:C (12.5%) and T:A>A:T (5.4%). This spectrum pattern differs from that in other solid tumors. TP53 mutations in the tumors at advanced stages were significantly more frequent compared with those in early-stage tumors. Additionally, age (<70 vs. ≥70 years) was significantly associated with CTNNB1 mutations. Using NGS, a number of novel gene mutations were identified in HCC, including established mutations and disproved mutations. The results of the present study offer new insight and improved understanding of the etiology and the development of HCC.

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Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing

Cited by 173 publications

References 43 publications

Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer

Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer

TERT promoter mutations in melanoma survival

Targeted sequencing of cancer‑associated genes in hepatocellular carcinoma using next‑generation sequencing

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