Genetic profile of<i>GNAQ</i>-mutated blue melanocytic neoplasms reveals mutations in genes linked to genomic instability and the PI3K pathway

Pérez-Alea, Mileidys; Vivancos, Ana; Caratù, Ginevra; Matito, Judit; Ferrer, Berta; Hernández-Losa, Javier; Cortés, Javier; Muñoz, Eva; García‐Patos, Vicente; Recio, Juan A.

doi:10.18632/oncotarget.8578

Cited by 20 publications

(13 citation statements)

References 37 publications

(61 reference statements)

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“…13,26,30,33,34 The diagnosis of ocular melanoma is particularly strongly associated (OR = 2.09, p < 0.0001) which is consistent with previous literature findings. 21,22,31 …”

Section: Resultssupporting

confidence: 91%

“…At the Bonferroni corrected p-value cutoff of 0.05 of 18 = 0.0028, KRAS is no longer significantly associated with GNA*, but the other features (ocular melanoma, appendiceal cancer, AURKA, SRC, CBL and LYN) remain significantly associated, in alignment with 13,26,30,33,34 The diagnosis of ocular melanoma is particularly strongly associated (OR = 2.09, P<.0001) which is consistent with previous literature findings. 21,22,31 Treatment regimens and GNA* alterations By using the longest measured (best) progression free survival as an outcome, we ran a Cox proportional hazards model of PFS versus treatment for various treatment regimens, including VEGF inhibitors, taxanes, capecitabine/ gemcitabine, platins and hormonal agents.…”

Section: Characteristics Independently Associated With Gna* Alterationssupporting

confidence: 89%

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GNAS, GNAQ,andGNA11alterations in patients with diverse cancers

Parish

Nguyen

Goodman

et al. 2018

Cancer

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“…13,26,30,33,34 The diagnosis of ocular melanoma is particularly strongly associated (OR = 2.09, p < 0.0001) which is consistent with previous literature findings. 21,22,31 …”

Section: Resultssupporting

confidence: 91%

Section: Characteristics Independently Associated With Gna* Alterationssupporting

confidence: 89%

GNAS, GNAQ,andGNA11alterations in patients with diverse cancers

Parish

Nguyen

Goodman

et al. 2018

Cancer

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“…The remaining shared genes, ARID2 and KMT2C, although present in only a small fraction of UM, may warrant further investigations to determine their significance. Both are known to undergo inactivation in melanocytic lesions [81,91]. ARID2 encodes for part of a chromatin remodeling complex, and is significantly mutated in CM with a high fraction of C>T transitions, characteristic of a UVB-induced mutation [85].…”

Section: Discussionmentioning

confidence: 99%

“…ARID2 encodes for part of a chromatin remodeling complex, and is significantly mutated in CM with a high fraction of C>T transitions, characteristic of a UVB-induced mutation [85]. KMT2C encodes a histone methyltransferase to regulate genomic instability and epigenetic changes [91], however it has not been explicitly associated with UV radiation to date. higher rates in CM than UM.…”

Section: Discussionmentioning

confidence: 99%

Presence and prevalence of UV related genetic mutations in uveal melanoma: similarities with cutaneous melanoma

Goh

Ramlogan‐Steel

Jenkins

et al. 2020

neo

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Ultraviolet (UV) radiation is an accepted etiological factor in cutaneous melanoma (CM), however its role in Uveal Melanoma (UM) is controversial. Partly as a consequence, CM and UM are often considered to be separate conditions, and advances in the treatment of CM have not led to joint clinical trials or parallel improvements in survival of UM. This study hypothesized that a subset of UM tumors display evidence of genetic changes consistent with UV-related damage similar to that shown in CM. Analysis of the Broad Institute Firebrowse depository of 80 UM samples and 343 CM samples, together with the Sanger Ins cer depository of 995 UM and 12,447 CM samples was undertaken to identify the most frequently mutated genes, mutation types and specific nucleotide variants (SNVs) in each condition. Somatic mutation data was cross-correlated and shared mutations assessed against known effects of UV radiation. The proportion of samples with C>T substitutions (a classic genetic marker of UV-related damage) was higher in UM than CM on both DNA strands (17.0% vs 13.1% , p = 0.038). The most frequently encountered cross-correlated mutated genes between UM and CM were, in order, BRAF, NRAS, TP53, CDKN2A, TERT, PTEN, ARID2 and KMT2C, with multiple common BRAF point mutations. Each cross-correlated mutation, and each common point mutation in BRAF, was associated with UV-related mechanistic changes. These findings support the hypothesis that the etiology of a substantial minority of UMs may be more UV dependent than previously recognized. Key words: uveal melanoma, cutaneous melanoma, ultraviolet radiation Cutaneous melanoma (CM) is the most common type of melanoma, accounting for more than 90% of melanomas worldwide. In comparison, the uveal tract gives rise to only 5% of melanomas, despite being the second most common site of origin. As a considerably more prevalent and studied disease,

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“…11 A number of studies have further demonstrated mutations or protein loss of the tumor suppressor BAP1 occurring in malignant blue nevi. 5,12,13 …”

mentioning

confidence: 99%

Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi

Möller¹,

Murali

Müller

et al. 2017

Modern Pathology

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Blue nevi are common melanocytic tumors arising in the dermal layer of the skin. Similar to uveal melanomas, blue nevi frequently harbor GNAQ and GNA11 mutations. Recently, recurrent CYSLTR2 and PLCB4 mutations were identified in uveal melanomas not harboring GNAQ or GNA11 mutations. All four genes (GNAQ, GNA11, CYSLTR2, and PLCB4) code for proteins involved in the same signaling pathway, which is activated by mutations in these genes. Given the related functional consequences of these mutations and the known genetic similarities between uveal melanoma and blue nevi, we analyzed a cohort of blue nevi to investigate whether CYSLTR2 and PLCB4 mutations occur in tumors lacking GNAQ or GNA11 mutations (as in uveal melanoma). A targeted next-generation sequencing assay covering known activating mutations in GNAQ, GNA11, CYSLTR2, PLCB4, KIT, NRAS, and BRAF was applied to 103 blue nevi. As previously reported, most blue nevi were found to harbor activating mutations in GNAQ (59%, n = 61), followed by less frequent mutations in GNA11 (16%, n = 17). Additionally, one BRAF (1%) and three NRAS (3%) mutations were detected. In three tumors (3%) harboring none of the aforementioned gene alterations, CYSLTR2 mutations were identified. All three CYSLTR2 mutations were the same c.386T > A, L129Q mutation previously identified in uveal melanoma that has been shown to lead to increased receptor activation and signaling. In summary, our study identifies CYSLTR2 L129Q alterations as a previously unrecognized activating mutation in blue nevi, occuring in a mutually exclusive fashion with known GNAQ and GNA11 mutations. Similar to GNAQ and GNA11 mutations, CYSLTR2 mutations, when present, are likely defining pathogenetic events in blue nevi.

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Genetic profile ofGNAQ-mutated blue melanocytic neoplasms reveals mutations in genes linked to genomic instability and the PI3K pathway

Cited by 20 publications

References 37 publications

GNAS, GNAQ,andGNA11alterations in patients with diverse cancers

GNAS, GNAQ,andGNA11alterations in patients with diverse cancers

Presence and prevalence of UV related genetic mutations in uveal melanoma: similarities with cutaneous melanoma

Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi

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