<i>NRAS</i> and <i>EPHB6</i> mutation rates differ in metastatic melanomas of patients in the North Island versus South Island of New Zealand

Jones, Angela; Ferguson, Peter M.; Gardner, Jacqui; Rooker, Serena; Sutton, T.; Ahn, Antonio; Chatterjee, Aniruddha; Bickley, Vivienne M.; Sarwar, Makhdoom; Emanuel, Patrick O.; Kenwright, Diane; Shepherd, Peter R.; Eccles, Michael R.

doi:10.18632/oncotarget.9351

Cited by 7 publications

(4 citation statements)

References 43 publications

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“…In the search of additional potential initiator mutations in GNAQ/GNA11 wildtype tumors, we focused on the protein tyrosine kinase 2 beta (PTK2B) gene given the central role of PTK2B in many intracellular signaling cascades including mitogen activated (MAP)-kinase signaling [30] and the occurrence of mutations in CM including a hotspot in G414 [31,32,33]. In the dataset of Martin et al [11], we identified a G941D mutation in the PTK2B gene.…”

Section: Resultsmentioning

confidence: 99%

Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma

Piaggio

Tozzo

Bernardi

et al. 2019

Cancers

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Background: Uveal melanoma (UM), a rare cancer of the eye, is characterized by initiating mutations in the genes G-protein subunit alpha Q (GNAQ), G-protein subunit alpha 11 (GNA11), cysteinyl leukotriene receptor 2 (CYSLTR2), and phospholipase C beta 4 (PLCB4) and by metastasis-promoting mutations in the genes splicing factor 3B1 (SF3B1), serine and arginine rich splicing factor 2 (SRSF2), and BRCA1-associated protein 1 (BAP1). Here, we tested the hypothesis that additional mutations, though occurring in only a few cases (“secondary drivers”), might influence tumor development. Methods: We analyzed all the 4125 mutations detected in exome sequencing datasets, comprising a total of 139 Ums, and tested the enrichment of secondary drivers in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that also contained the initiating mutations. We searched for additional mutations in the putative secondary driver gene protein tyrosine kinase 2 beta (PTK2B) and we developed new mutational signatures that explain the mutational pattern observed in UM. Results: Secondary drivers were significantly enriched in KEGG pathways that also contained GNAQ and GNA11, such as the calcium-signaling pathway. Many of the secondary drivers were known cancer driver genes and were strongly associated with metastasis and survival. We identified additional mutations in PTK2B. Sparse dictionary learning allowed for the identification of mutational signatures specific for UM. Conclusions: A considerable part of rare mutations that occur in addition to known driver mutations are likely to affect tumor development and progression.

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Section: Resultsmentioning

confidence: 99%

Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma

Piaggio

Tozzo

Bernardi

et al. 2019

Cancers

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“…Although enormous progress has been made in the successful treatment of advanced cutaneous melanoma using targeted therapy and immune checkpoint inhibitors, the response rates and outcomes in the setting of metastatic mucosal melanoma are less promising. In particular, there is very limited knowledge about the use of targeted therapies in the treatment of primary mucosal melanoma [ 4 , 5 ].…”

Section: Discussionmentioning

confidence: 99%

Treatment of Primary and Metastatic Multifocal Mucosal Melanoma of the Oral Cavity with Imatinib

Deinlein¹,

Wolf²,

Rainer³

et al. 2017

Case Rep Oncol

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Background: Mucosal melanoma of the oral cavity is a rare entity and accounts for less than 1–3% of all melanomas. Contrary to cutaneous melanoma, primary oral melanoma more commonly harbors mutations in c-KIT. Methods: A 64-year-old man presented with asymptomatic, multiple, brown-to-black macules in the oral cavity. A biopsy was taken and histopathology exhibited mucosal melanoma. In molecular analysis, a c-KIT mutation was proven and a CT scan revealed pulmonary metastases. Due to the multifocality of the lesions, the metastases, and the mutation status, a therapy with imatinib was initiated. Results: After 1 year of therapy, progressive disease in the lung was noticed. Therefore, the therapy was switched to a PD-1 antagonist and a CTL-4 antibody. Conclusions: Our case suggests that imatinib may be considered as first-line treatment for both locally advanced and distant primary multifocal oral melanoma, for which surgery or radiotherapy of the primary tumor is impossible.

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“…BRAF mutations are the most common ( Fig . b ), present in 30–50 per cent of cutaneous melanomas, followed by NRAS (25 per cent) and NF1 (less than 10 per cent) mutations. All three strongly associate with genetic signatures of an ultraviolet (UV) radiation effect, whereas less than 30 per cent of melanomas lacking any of these mutations (triple wild‐type) show UV signatures.…”

Section: Genomic Basis For Advances In Systemic Therapymentioning

confidence: 99%

“…Immunohistochemistry can serve as a quick screen, with excellent sensitivity for the BRAF V600E mutation. If immunohistochemistry is negative, alternative forms of testing are required to screen for other treatable mutations in BRAF (such as V600K, present in 10–20 per cent of the BRAF ‐mutant melanoma population) and other genes. Assays using multiplex PCR can amplify multiple targets in one test.…”

Section: Genomic Testing To Guide Treatment Of Metastatic Diseasementioning

confidence: 99%

Impact of genomics on the surgical management of melanoma

Ferguson

Long

Scolyer

et al. 2018

British Journal of Surgery

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Background: Although surgery for early-stage melanoma offers the best chance of cure, recent advances in molecular medicine have revolutionized the management of late-stage melanoma, leading to significant improvements in clinical outcomes. Research into the genomic drivers of disease and cancer immunology has not only ushered in a new era of targeted and immune-based therapies for patients with metastatic melanoma, but has also provided new tools for monitoring disease recurrence and selecting therapeutic strategies. These advances present new opportunities and challenges to the surgeon treating patients with melanoma. Methods:The literature was reviewed to evaluate diagnostic and therapeutic advances in the management of cutaneous melanoma, and to highlight the impact of these advances on surgical decision-making.Results: Genomic testing is not required in the surgical management of primary melanoma, although it can provide useful information in some situations. Circulating nucleic acids from melanoma cells can be detected in peripheral blood to predict disease recurrence before it manifests clinically, but validation is required before routine clinical application. BRAF mutation testing is the standard of care for all patients with advanced disease to guide therapy, including the planning of surgery in adjuvant and neoadjuvant settings.Conclusion: Surgery remains central for managing primary melanoma, and is an important element of integrated multidisciplinary care in advanced disease, particularly for patients with resectable metastases. The field will undergo further change as clinical trials address the relationships between surgery, radiotherapy and systemic therapy for patients with high-risk, early-stage and advanced melanoma.

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NRAS and EPHB6 mutation rates differ in metastatic melanomas of patients in the North Island versus South Island of New Zealand

Cited by 7 publications

References 43 publications

Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma

Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma

Treatment of Primary and Metastatic Multifocal Mucosal Melanoma of the Oral Cavity with Imatinib

Impact of genomics on the surgical management of melanoma

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