Exome sequencing identifies GRIN2A as frequently mutated in melanoma

Wei, Xiaomu; Walia, Vijay; Lin, Jimmy; Teer, Jamie K.; Prickett, Todd D.; Gartner, Jared J.; Davis, Sean; Program, Nisc Comparative Sequencing; Stemke-Hale, Katherine; Davies, Michael A.; Gershenwald, Jeffrey E.; Robinson, William A.; Robinson, Steven E.; Rosenberg, Steven A.; Samuels, Yardena

doi:10.1038/ng.810

Cited by 437 publications

(422 citation statements)

References 32 publications

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“…However, this observation led us to the discovery of a second unique finding, amplification of GRIN2A, in a subset of TCC-UB. Previous findings of GRIN2A as a frequently mutated gene in melanoma (49) and a frequently overexpressed gene in ALK-positive lung cancer (50), as well as the recent recognition that glutamate transport and intermediary metabolism may be important in the etiology of other tumors (glioblastoma) (38), provide convincing evidence that GRIN2A is of importance in cancer.…”

Section: Discussionmentioning

confidence: 95%

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

Morrison

Liu

Woloszynska‐Read³

et al. 2014

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

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Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.2 per megabase), structural variants (SVs; average of 46), or both. This group was best characterized by chromothripsis and the presence of subclonal populations of neoplastic cells or intratumoral mutational heterogeneity. Here, we provide evidence that the process of chromothripsis in TCC-UB is mediated by nonhomologous end-joining using kilobase, rather than megabase, fragments of DNA, which we refer to as "stitchers," to repair this process. We postulate that a potential unifying theme among tumors with the more complex genotype group is a defective replication-licensing complex. A second group (two bladder tumors) had no chromothripsis, and a simpler genotype, WT tumor protein p53, had relatively few SNVs (average of 5.9 per megabase) and only a single SV. There was no evidence of a subclonal population of neoplastic cells. In this group, we used a preclinical model of bladder carcinoma cell lines to study a unique SV (translocation and amplification) of the gene glutamate receptor ionotropic N-methyl D-aspertate as a potential new therapeutic target in bladder cancer.next-generation sequencing | tumor heterogeneity | GRIN2A | replication

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Section: Discussionmentioning

confidence: 95%

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

Morrison

Liu

Woloszynska‐Read³

et al. 2014

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

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“…Newer high-throughput sequencing methods for tumors have allowed studies to identify many additional somatic mutations in melanomas [103,110,128,156,239], including NF1 and RAC1 mutations (5 % of cases) and BRAF gene fusions [35,110]. Recently, it was also discovered that 30-40 % of melanomas harbor mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene, and these TERT promoter mutations were found to occur more frequently in BRAF-mutant melanomas [101,105,108,107].…”

Section: Somatic Genetic Factors: Tumor Subtypesmentioning

confidence: 99%

Melanoma Epidemiology and Prevention

Berwick

Buller

Cust

et al. 2015

Cancer Treatment and Research

122

121

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The epidemiology of melanoma is complex, and individual risk depends on sun exposure, host factors, and genetic factors, and in their interactions as well. Sun exposure can be classified as intermittent, chronic, or cumulative (overall) exposure, and each appears to have a different effect on type of melanoma. Other environmental factors, such as chemical exposures-either through occupation, atmosphere, or food-may increase risk for melanoma, and this area warrants further study. Host factors that are well known to be important are the numbers and types of nevi and the skin phenotype. Genetic factors are classified as

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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

107

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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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Exome sequencing identifies GRIN2A as frequently mutated in melanoma

Cited by 437 publications

References 32 publications

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

Melanoma Epidemiology and Prevention

TERT promoter mutations in melanoma survival

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