Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas

Krauthammer, Michael; Kong, Yong; Bacchiocchi, Antonella; Evans, Perry; Pornputtapong, Natapol; Wu, Cen; McCusker, James P.; Ma, Shuangge; Cheng, Elaine; Straub, Robert; Serin, Merdan; Bosenberg, Marcus W.; Ariyan, Stephan; Narayan, Deepak; Sznol, Mario; Kluger, Harriet M.; Mane, Shrikant; Schlessinger, Joseph; Lifton, Richard P.; Halaban, Ruth

doi:10.1038/ng.3361

Cited by 346 publications

(400 citation statements)

References 68 publications

Supporting

Mentioning

366

Contrasting

Unclassified

Order By: Relevance

“…Indeed, most of the differentially mutated genes, cancer driver genes, and pathways identified in the present study had the highest mutation frequency in the NF1 subtype as compared to the other genomic subtypes. Herein, we confirmed that mutations in the RASopathy genes RASA2 and PTPN11 were enriched in the NF1 subtype (Krauthammer et al ., 2015) and also identified RASSF2 , a RAS domain‐containing gene, as enriched in the NF1 subtype. These results further support that NF1 cooperates with other RASopathy genes in melanomagenesis.…”

Section: Discussionmentioning

confidence: 95%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 95%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The samples were collected by the Tissue Resource Core of the Yale SPORE in Skin Cancer with the participant's signed informed consent according to Health Insurance Portability and Accountability Act (HIPAA) regulations with a Human Investigative Committee protocol as described (Krauthammer et al 2015). Peripheral blood lymphocytes (PBL) were isolated from blood obtained 2 mo after tumor excision.…”

Section: Normal Ex Vivo Clone Generation Experimentsmentioning

confidence: 99%

A generic, cost-effective, and scalable cell lineage analysis platform

et al. 2016

Self Cite

View full text Add to dashboard Cite

Advances in single-cell genomics enable commensurate improvements in methods for uncovering lineage relations among individual cells. Current sequencing-based methods for cell lineage analysis depend on low-resolution bulk analysis or rely on extensive single-cell sequencing, which is not scalable and could be biased by functional dependencies. Here we show an integrated biochemical-computational platform for generic single-cell lineage analysis that is retrospective, cost-effective, and scalable. It consists of a biochemical-computational pipeline that inputs individual cells, produces targeted single-cell sequencing data, and uses it to generate a lineage tree of the input cells. We validated the platform by applying it to cells sampled from an ex vivo grown tree and analyzed its feasibility landscape by computer simulations. We conclude that the platform may serve as a generic tool for lineage analysis and thus pave the way toward large-scale human cell lineage discovery.

show abstract

“…6 Receptor tyrosine kinases (RTK) or RAS-GTP can activate the PI3K-AKT pathway, while PTEN is a negative regulator, mutation of which leads to constitutive activation of AKT and is followed by changes in cell growth, motility and invasion. 124 wt melanomas analyzed by Krauthammer et al 8 Interestingly, around 60% of these melanomas harbored comutations in RAS-opathy genes (RASA2, PTPN11, SOS1, RAF1 and SPRED1), 8,16 which are known to be linked with Noonan, Leopard and Legius syndromes. 8 Melanomas referred to as triple wt show none of the three previously mentioned mutations.…”

Section: Genetic Landscape Of Mutationsmentioning

confidence: 99%

“…7,8,11 This causes constitutive activation of BRAF protein, which results in increased proliferation and survival of melanoma cells. 12 In more than 90% of cases valine is substituted with glutamate at codon 600 (V600E), less frequently with lysine (V600K) or arginine (V600R).…”

Section: Genetic Landscape Of Mutationsmentioning

confidence: 99%

“…13 NF1 negatively regulates RAS by increasing RAS GTPase activity and hence turning RAS-GTP to RAS-GDP. 8 Active RAS leads to activation of BRAF (dimerization of non-mutated BRAF; BRAF V600E mutated protein can be active as a monomer) and subsequently MEK. This cascade concludes in activation of ERK1 and ERK2, which can then translocate to the nucleus and regulate MITF, c-MYC and other transcription factors, resulting in alteration of cell proliferation and senescence.…”

Section: Genetic Landscape Of Mutationsmentioning

confidence: 99%

See 1 more Smart Citation

Developments in targeted therapy in melanoma

Amann

Ramelyte

Thurneysen

et al. 2017

European Journal of Surgical Oncology (EJSO)

View full text Add to dashboard Cite

Melanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations). The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent longterm outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy. AbstractMelanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations).The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent long-term outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy.

show abstract

Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas

Cited by 346 publications

References 68 publications

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

A generic, cost-effective, and scalable cell lineage analysis platform

Developments in targeted therapy in melanoma

Contact Info

Product

Resources

About