Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

Krauthammer, Michael; Kong, Yong; Ha, Byung Hak; Evans, Perry; Bacchiocchi, Antonella; McCusker, James P.; Cheng, Elaine; Davis, Matthew J.; Goh, Gerald; Choi, Murim; Ariyan, Stephan; Narayan, Deepak; Dutton‐Regester, Ken; Capatana, Ana; Holman, Edna C.; Bosenberg, Marcus W.; Sznol, Mario; Kluger, Harriet M.; Brash, Douglas E.; Stern, David F.; Materin, Miguel A.; Lo, Roger S.; Mane, Shrikant; Ma, Shuangge; Kídd, Kenneth K.; Hayward, Nicholas K.; Lifton, Richard P.; Schlessinger, Joseph; Boggon, Titus J.; Halaban, Ruth

doi:10.1038/ng.2359

Cited by 1,061 publications

(1,200 citation statements)

References 81 publications

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“…The question of a clinically or biologically relevant melanoma classification based on molecular tumor features is a long‐standing problem. Several reports have suggested classification based on mutation status of key genes in the MAPK signaling pathway and/or sun exposure pattern (Curtin et al ., 2005; Krauthammer et al ., 2012). The present study provides extensive characterization of genomic subtypes based on mutations in BRAF , RAS , and NF1 by using a large dataset comprising mutation data for 1461 genes in 864 clinically annotated melanomas.…”

Section: Discussionmentioning

confidence: 99%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

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In general, melanoma can be considered as a UV‐driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen‐activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF,RAS,NF1 mutation or triple‐wild‐type status and correlated with tumor and patient characteristics. We found that the NF1‐mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co‐occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain‐containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1‐mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease‐specific survival, DSS; HR, 1.9; 95% CI, 1.21–3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28–2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.

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Section: Discussionmentioning

confidence: 99%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

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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%

“…NRAS-mutant melanomas are associated with older age at diagnosis, but less associated with specific anatomic location, are more likely to be nodular subtype, and show increased Breslow thickness and presence of mitoses [60,63,64,86,139,228,231,234]. Interestingly, RAC1-mutant melanomas are more common in older men on the head and neck location [128], while TERT promoter mutations in melanomas are associated with older age, increased Breslow thickness, nodular subtype, and tumor ulceration [101].…”

Section: Clinical Characteristics Of Tumor Subtypesmentioning

confidence: 99%

“…Furthermore, PTEN mutations occur in approximately 50 % of melanomas from xeroderma pigmentosum patients, who are susceptible to UV mutagenesis, while BRAF, NRAS, and KIT mutation frequencies were lower than PTEN [160]. Next-generation sequencing has more recently identified UVB signature hot spot mutations in putative oncogenes, including at PPP6C R264C, STK19 D89N, and RAC1 P29S [103,128]. In addition, TERT promoter mutations in melanoma, also UVB signature mutations, are more frequent at both chronically and intermittently sun-exposed than non-exposed sites, although these mutations were not associated with reported sun behavior [101].…”

Section: Sun Exposure and Tumor Subtypesmentioning

confidence: 99%

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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 recurrent somatic RAC1 mutations in melanoma

Cited by 1,061 publications

References 81 publications

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

Melanoma Epidemiology and Prevention

TERT promoter mutations in melanoma survival

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