NF1 mutations in conjunctival melanoma

Scholz, Simone L.; Cosgarea, Ioana; Süßkind, Daniela; Murali, Rajmohan; Möller, Inga; Reis, Henning; Leonardelli, Sonia; Schilling, Bastian; Schimming, Tobias; Hadaschik, Eva; Franklin, Cindy; Paschen, Annette; Sucker, Antje; Steuhl, K.–P.; Schadendorf, Dirk; Westekemper, Henrike; Griewank, Klaus G.

doi:10.1038/s41416-018-0046-5

Cited by 63 publications

(93 citation statements)

References 44 publications

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“…Third, BRAF and NRAS mutations were tested by different techniques, and, as a result, their rarer mutations might have been missed in a small number of cases. In addition, it is possible that tumors that were both BRAF wt and NRAS wt harbor NF1 or other RAS mutations, which were reported only after the completion of the current work (Scholz et al, ). A follow‐up study that incorporates all known CoM mutations is now needed to understand their significance in CoM pathogenesis.…”

Section: Discussionmentioning

confidence: 87%

“…These recent findings are also consistent with CM where NF1 mutations occur in 12%–30%, and are generally mutually exclusive from tumors with BRAF and NRAS mutations (Cirenajwis et al, ; Hodis et al, ; Krauthammer et al, ). In line with CM, a 4‐group gene‐specific mutation/triple wild type (wt) classification for CoM was proposed (Cancer Genome Atlas, Network, ; Scholz et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Lake et al did not reveal any association between 6p21.2 gains and histological cell type, age, sex, or survival (Lake et al, ). In addition, no correlation between BRAF, NRAS or NF1 mutations and recurrence, metastasis, or mortality was found (Gear et al, ; Griewank et al, ; Lake et al, ; Larsen et al, ; Scholz et al, ; Sheng et al, ). A strong association between BRAF mutation and sun exposure was determined in two reports ( p ≤ 0.03; Griewank et al, ; Larsen et al, ), and with clinical and pathological T1 stage ( p = 0.007) in a single study (Larsen et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies investigating CoM genetic abnormalities had variable, and often small, cohort sizes (n = 16-78), and mostly targeted hotspot mutations known to occur in cutaneous melanoma (CM), namely in BRAF, NRAS, KIT, and the TERT promoter described in on average 40%-50%, 15%-25%, 1%-3%, and ~70% of CM cases, respectively (Broekaert et al, 2010;Carr & Mackie, 1994;Curtin, Busam, Pinkel, & Bastian, 2006;Davies et al, 2002;Handolias et al, 2010;Horn et al, 2013;Huang et al, 2013;Moltara et al, 2018;van 't Veer et al, 1989). In CoM, such mutations are reported in 8%-54%, 0%-18%, 0%-11%, and 32%, respectively (Beadling et al, 2008;El-Shabrawi, Radner, Muellner, Langmann, & Hoefler, 1999;Gear, Williams, Kemp, & Roberts, 2004;Goldenberg-Cohen et al, 2005;Griewank et al, 2013;Lake et al, 2011;Larsen et al, 2015;Populo, Soares, Rocha, Silva, & Lopes, 2010;Scholz et al, 2018;Spendlove et al, 2004). Whole exome sequencing on a relatively small series of 5 CoMs identified mutually exclusive NF1, BRAF, and NRAS driver mutations in 20%, 60%, and 20% of samples, respectively, alongside other individual cancer-associated and epigenetic regulator mutations, such as those of EGFR and the TERT promoter (Swaminathan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Most recently, a larger study using next-generation sequencing discovered mutations of NF1 in 21 of 63 (33%) CoMs, BRAF in 16 (25%), NRAS in 11 (17%), and KRAS in a single sample (Scholz et al, 2018). Mutations in NF1 were mostly mutually exclusive with those in BRAF or NRAS although exact frequencies were not given (Scholz et al, 2018). These recent findings are also consistent with CM where NF1 mutations occur in 12%-30%, and are generally mutually exclusive from tumors with BRAF and NRAS mutations (Cirenajwis et al, 2017;Hodis et al, 2012;Krauthammer et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome

Kenawy

Kalirai

Sacco

et al. 2019

Pigment Cell Melanoma Res

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Relatively little is known about the genetic aberrations of conjunctival melanomas (CoM) and their correlation with clinical and histomorphological features as well as prognosis. The aim of this large collaborative multicenter study was to determine potential key biomarkers for metastatic risk and any druggable targets for high metastatic risk CoM. Using Affymetrix single nucleotide polymorphism genotyping arrays on 59 CoM, we detected frequent amplifications on chromosome (chr) 6p and deletions on 7q, and characterized mutation‐specific copy number alterations. Deletions on chr 10q11.21‐26.2, a region harboring the tumor suppressor genes, PDCD4, SUFU, NEURL1, PTEN, RASSF4, DMBT1, and C10orf90 and C10orf99, significantly correlated with metastasis (Fisher's exact, p ≤ 0.04), lymphatic invasion (Fisher's exact, p ≤ 0.02), increasing tumor thickness (Mann–Whitney, p ≤ 0.02), and BRAF mutation (Fisher's exact, p ≤ 0.05). This enhanced insight into CoM biology is a step toward identifying patients at risk of metastasis and potential therapeutic targets for systemic disease.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome

Kenawy

Kalirai

Sacco

et al. 2019

Pigment Cell Melanoma Res

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Integrative Exome and Transcriptome Analysis of Conjunctival Melanoma and Its Potential Application for Personalized Therapy

Demirci

Ciftci

et al. 2019

JAMA Ophthalmol

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IMPORTANCE Greater understanding of molecular features of conjunctival melanoma (CM) may improve its clinical management. OBJECTIVE To evaluate molecular features of CM and application of this information into clinical care. DESIGN, SETTING, AND PARTICIPANTSIn a prospective case series of CM with integrative exome and transcriptome analysis, 8 patients at an academic ocular oncology setting were evaluated. The study was conducted from November 2015 to March 2018. INTERVENTIONS/EXPOSURESIntegrative exome and transcriptome analysis of CMs and clinical management of a patient's care by using this information. MAIN OUTCOMES AND MEASURES Molecular characterization of CM and its potential clinical application. RESULTSIn the 8 patients (4 men) included in analysis, 4 subgroups of CM were observed, including the BRAF V600E mutation in 1 tumor, NRAS Q61R mutation in 3 tumors, NF1 mutations (Q1188X, R440X, or M1215K+ S15fs) in 3 tumors, and triple-wild type (triple-WT) in 1 tumor. The triple-WT case had CCND1 amplification and mutation in the CIC gene (Q1508X). Five tumors, including the triple-WT, also harbored mutations in MAPK genes. In addition to the genes linked to mitogen-activated protein kinase and phosphoinositol 3-kinase pathways, those involved in cell cycle and/or survival, ubiquitin-mediated protein degradation, and chromatin remodeling/epigenetic regulation (ATRX being the most frequently mutated: noted in 5 tumors) may play an important role. Other frequently mutated genes included PREX2 (n = 3), APOB (n = 4), and RYR1/2 (n = 4), although their relevance remains to be determined. The mutation burden ranged from 1.1 to 15.6 mutations per megabase (Mut/Mb) and was 3.3 Mut/Mb or less in 3 tumors and more than 10 Mut/Mb in 2 tumors. A patient with a large tumor and BRAF V600E mutation was treated with combined systemic BRAF (dabrafenib) and MEK (trametinib) inhibitors. After 3 months of therapy, her CM responded substantially and the residual tumor was removed by local surgical excision. CONCLUSIONS AND RELEVANCEThe NRAS Q61R and NF1 mutations were more common than the BRAF V600E mutation in this series. Although small tumors (where incisional biopsy is not indicated) are treated with surgical excision regardless of mutational profile, in large tumors carrying the BRAF V600E mutation, neoadjuvant therapy with combined systemic BRAF and MEK inhibitors followed by local excision may be used as an alternative to exenteration. Integrative omics analysis of CM may be informative and guide clinical management and treatment in selected cases.

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Conjunctival and Corneal Tumors: Melanoma

Pe’er¹,

Folberg²

2019

Clinical Ophthalmic Oncology

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NF1 mutations in conjunctival melanoma

Cited by 63 publications

References 44 publications

Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome

Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome

Integrative Exome and Transcriptome Analysis of Conjunctival Melanoma and Its Potential Application for Personalized Therapy

Conjunctival and Corneal Tumors: Melanoma

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