FBXW7 Mutations in Melanoma and a New Therapeutic Paradigm

Aydin, Iraz T.; Melamed, Rachel D.; Adams, Sarah J.; Castillo-Martin, Mireia; Yorulmaz, Ahu; Bryk, Diana; Brunner, Georg; Cordon‐Cardo, Carlos; Osman, Iman; Rabadán, Raúl; Çelebi, Jülide Tok

doi:10.1093/jnci/dju107

Cited by 76 publications

(84 citation statements)

References 30 publications

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“…Additionally, high Notch1 expression has been reported to be related to poor overall survival rates in colorectal, breast cancer and HCC (49,50). Latest studies proved that Notch1, as the substrate of Fbxw7 which can inhibit melanoma cell migration, was activated to promote melanoma angiogenesis and tumor growth through Fbxw7 silencing (30). However, whether Fbxw7/Notch1 axis participates in the process of metastasis and invasion in HCC remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies in our laboratory showed that downregulation of Notch1 decreased the migration and invasion capacities of HCC cells via the COX-2 and ERK1/2 pathways (29). Latest studies proved that Notch1, as the substrate of Fbxw7, which can inhibit melanoma cell migration, was activated to promote melanoma angiogenesis and tumor growth through Fbxw7 silencing (22,30). However, whether Fbxw7/Notch1 axis participates in the process of metastasis and invasion in HCC remains unclear.…”

Section: Fbxw7 Regulates Hepatocellular Carcinoma Migration and Invasmentioning

confidence: 98%

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Fbxw7 regulates hepatocellular carcinoma migration and invasion via Notch1 signaling pathway

Wang

Zhang²,

Zhou³

et al. 2015

International Journal of Oncology

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Abstract. Hepatocellular carcinoma (HCC) is one of the most common human malignancies and also the leading cause of cancer-related death in the world. The mechanisms underlying the progression and metastasis of HCC remain unclear. The E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (Fbxw7) is broadly considered as a tumor suppressor gene. However, the role of Fbxw7 in HCC is not clear. To investigate the expression and biological functions of Fbxw7 in HCC, we examined Fbxw7 expression level using HCC tissue microarray and immunohistochemistry. Our data showed that Fbxw7 expression is significantly reduced in HCC compared with non-cancerous tissues (P<0.05). Fbxw7 levels were significantly associated with tumor differentiation (P= 0.013), the incidence of portal or hepatic venous invasion (P=0.031), metastasis (P= 0.027) and AJCC cancer stage (P= 0.047). Then, we observed a strong correlation between low Fbxw7 expression and a worse 5-year survival of HCC patients (P<0.001). Furthermore, multivariate Cox regression analyses demonstrated that the Fbxw7 expression (P<0.001) was an independent factor for the prediction of the overall survival of HCC patients. We also found that both Fbxw7 mRNA and protein levels were significantly reduced in HCC cell lines compared with human liver non-tumor cell line. Moreover, our in vitro experiments showed a remarkable increase of cell migration and invasion in Fbxw7-knockdown cells and a decrease in Fbxw7-overexpress cells. In addition, the present study demonstrated that Fbxw7 is involved in the migration and invasion of HCC cells via regulating Notch1 and the downstream molecules of Notch1. Taken together, our findings indicate that Fbxw7 can be used as a prognostic marker; it has an important role in HCC progression and inhibits HCC cell migration and invasion through the Notch1 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Fbxw7 Regulates Hepatocellular Carcinoma Migration and Invasmentioning

confidence: 98%

Fbxw7 regulates hepatocellular carcinoma migration and invasion via Notch1 signaling pathway

Wang

Zhang²,

Zhou³

et al. 2015

International Journal of Oncology

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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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“…Lessons learned from FBXW7-associated murine cancer models also convincingly demonstrated that it is a bona fide tumor suppressor gene with extensive functions [26]. Recent genetic profiles of human cancers based on high-throughput sequencing revealed that FBXW7 is among the most frequently mutated cancer genes [28][29][30][31][32][33]. Thus, FBXW7 has been illuminated to be a central mediator in tumorigenesis [34].…”

Section: Discussionmentioning

confidence: 97%