Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma

Gartner, Jared J.; Parker, Stephen C. J.; Prickett, Todd D.; Dutton-Regester, K; Stitzel, Michael L.; Lin, Jimmy C.; Davis, Sean; Simhadri, Vijaya L.; Jha, Sujata; Hamasaki-Katagiri, Nobuko; Gotea, Valer; Teer, Jamie K.; Wei, Xiaomu; Morken, Mario A.; Bhanot, Umesh; Guo, Chunfang; Elnitski, Laura; Davies, Michael A.; Gershenwald, Jeffrey E.; Carter, Hannah; Karchin, Rachel; Robinson, William A.; Robinson, Steven E.; Rosenberg, Steven A.; Collins, Francis S.; Parmigiani, Giovanni; Komar, Anton A.; Kimchi-Sarfaty, Chava; Hayward, Nicholas K.; Margulies, Elliott H.; Samuels, Yardena; Becker, Jesse; Benjamin, Betty; Blakesley, Robert W.; Bouffard, Gerry; Brooks, Shelise; Coleman, Holly; Dekhtyar, Mila; Gregory, Michael D.; Guan, Xiaobin; Gupta, Jyoti; Han, Joel; Hargrove, April; Ho, Shi-ling; Johnson, Taccara; Legaspi, Richelle; Lovett, Sean; Maduro, Quino; Masiello, Cathy; Maskeri, Baishali; McDowell, Jenny; Montemayor, Casandra; Mullikin, James C.; Park, Morgan; Riebow, Nancy L.; Schandler, Karen; Schmidt, Brian; Sison, Christina; Stantripop, Mal; Thomas, James E.; Thomas, Pam; Vemulapalli, Meg; Young, Alice

doi:10.1073/pnas.1304227110

Cited by 154 publications

(123 citation statements)

References 35 publications

Supporting

Mentioning

123

Contrasting

Order By: Relevance

“…More than 50 diseases have been linked to silent mutations in different proteins (Sauna and Kimchi-Sarfaty 2011). The first identified silent mutations were shown to affect the normal splicing pattern but, more recently, other important effects have been described (Fåhraeus et al 2016;Fernández-Calero et al 2016;Gartner et al 2013;Sauna and Kimchi-Sarfaty 2011;Lamolle et al 2006;Hunt et al 2014).…”

Section: Translation Kineticsmentioning

confidence: 99%

Protein folding and tRNA biology

2017

View full text Add to dashboard Cite

Polypeptides can fold into tertiary structures while they are synthesized by the ribosome. In addition to the amino acid sequence, protein folding is determined by several factors within the cell. Among others, the folding pathway of a nascent polypeptide can be affected by transient interactions with other proteins, ligands, or the ribosome, as well as by the translocation through membrane pores. Particularly, the translation machinery and the population of tRNA under different physiological or adaptive responses can dramatically affect protein folding. This review summarizes the scientific evidence describing the role of translation kinetics and tRNA populations on protein folding and addresses current efforts to better understand tRNA biology. It is organized into three main parts, which are focused on: (i) protein folding in the cellular context; (ii) tRNA biology and the complexity of the tRNA population; and (iii) available methods and technical challenges in the characterization of tRNA pools. In this manner, this work illustrates the ways by which functional properties of proteins may be modulated by cellular tRNA populations.

show abstract

Section: Translation Kineticsmentioning

confidence: 99%

Protein folding and tRNA biology

2017

View full text Add to dashboard Cite

show abstract

“…However, recent studies have demonstrated that genes with synonymous mutations could also be driver genes and play important role in tumorigenesis 29,30 . Therefore, other genes in Table 2 could be potential driver genes as well.…”

Section: Mutationmentioning

confidence: 99%

Mutational landscape of intrahepatic cholangiocarcinoma

et al. 2014

View full text Add to dashboard Cite

“…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

107

View full text Add to dashboard Cite

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 (...

show abstract

Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma

Abstract: Blots were performed against DDR (p53 pSer15, histone 2AX pSer139), cell survival/ cell death (AKT pThr308, cleaved PARP), and cell signaling (ERK1/2 pThr202/Tyr204) markers and controls. Actin and GAPDH served as loading controls.

Cited by 154 publications

References 35 publications

Protein folding and tRNA biology

Protein folding and tRNA biology

Mutational landscape of intrahepatic cholangiocarcinoma

TERT promoter mutations in melanoma survival

Contact Info

Product

Resources

About