Melanomas comprise multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative ...role of UV radiation, predisposing germ-line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain-of-function mutations in one of several primary oncogenes, which typically lead to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor-suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about the pathogenesis and clinical, histologic, and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework.
Germline copy number variants (CNVs) and somatic copy number alterations (SCNAs) are of significant importance in syndromic conditions and cancer. Massively parallel sequencing is increasingly used ...to infer copy number information from variations in the read depth in sequencing data. However, this approach has limitations in the case of targeted re-sequencing, which leaves gaps in coverage between the regions chosen for enrichment and introduces biases related to the efficiency of target capture and library preparation. We present a method for copy number detection, implemented in the software package CNVkit, that uses both the targeted reads and the nonspecifically captured off-target reads to infer copy number evenly across the genome. This combination achieves both exon-level resolution in targeted regions and sufficient resolution in the larger intronic and intergenic regions to identify copy number changes. In particular, we successfully inferred copy number at equivalent to 100-kilobase resolution genome-wide from a platform targeting as few as 293 genes. After normalizing read counts to a pooled reference, we evaluated and corrected for three sources of bias that explain most of the extraneous variability in the sequencing read depth: GC content, target footprint size and spacing, and repetitive sequences. We compared the performance of CNVkit to copy number changes identified by array comparative genomic hybridization. We packaged the components of CNVkit so that it is straightforward to use and provides visualizations, detailed reporting of significant features, and export options for integration into existing analysis pipelines. CNVkit is freely available from https://github.com/etal/cnvkit.
From melanocytes to melanomas Shain, A Hunter; Bastian, Boris C
Nature reviews. Cancer,
06/2016, Letnik:
16, Številka:
6
Journal Article
Recenzirano
Melanomas on sun-exposed skin are heterogeneous tumours, which can be subtyped on the basis of their cumulative levels of exposure to ultraviolet (UV) radiation. A melanocytic neoplasm can also be ...staged by how far it has progressed, ranging from a benign neoplasm, such as a naevus, to a malignant neoplasm, such as a metastatic melanoma. Each subtype of melanoma can evolve through distinct evolutionary trajectories, passing through (or sometimes skipping over) various stages of transformation. This Review delineates several of the more common progression trajectories that occur in the patient setting and proposes models for tumour evolution that integrate genetic, histopathological, clinical and biological insights from the melanoma literature.
Constitutive activation of Gαq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK. Protein kinase C (PKC) has been implicated as a link, but the ...mechanistic details remained unclear. We identified PKC δ and ɛ as required and sufficient to activate MAPK in GNAQ mutant melanomas. MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM. RasGRP3 activation occurs via PKC δ- and ɛ-dependent phosphorylation and PKC-independent, DAG-mediated membrane recruitment, possibly explaining the limited effect of PKC inhibitors to durably suppress MAPK in UM. The findings nominate RasGRP3 as a therapeutic target for cancers driven by oncogenic GNAQ/11.
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•PKC δ/ɛ mediate ERK activation in uveal melanoma with Gαq pathway mutations•The RAS exchange factor RasGRP3 is a critical module for ERK activation•PKC δ, PKC ɛ, and RasGRP3 are novel therapeutic targets for uveal melanoma
Chen et al. find that Ras is required for GNAQ-mediated MAPK activation and identify PKC δ,ɛ and RasGRP3 as components of a signaling module necessary and sufficient to activate the Ras/MAPK pathway in GNAQ mutant uveal melanoma (UM). RasGRP3 is selectively overexpressed in response to GNAQ/11 mutations in UM.
There have been major advances in the understanding of melanoma since the last revision of the World Health Organization (WHO) classification in 2006.
To discuss development of the 9 distinct types ...of melanoma and distinguishing them by their epidemiology, clinical and histologic morphology, and genomic characteristics. Each melanoma subtype is placed at the end of an evolutionary pathway that is rooted in its respective precursor, wherever appropriate and feasible, based on currently known data. Each precursor has a variable risk of progression culminating in its fully evolved, invasive melanoma.
This review is based on the "Melanocytic Tumours" section of the 4th edition of the
, published in 2018.
Melanomas were divided into those etiologically related to sun exposure and those that are not, as determined by their mutational signatures, anatomic site, and epidemiology. Melanomas on the sun-exposed skin were further divided by the histopathologic degree of cumulative solar damage (CSD) of the surrounding skin, into low and high CSD, on the basis of degree of associated solar elastosis. Low-CSD melanomas include superficial spreading melanomas and high-CSD melanomas incorporate lentigo maligna and desmoplastic melanomas. The "nonsolar" category includes acral melanomas, some melanomas in congenital nevi, melanomas in blue nevi, Spitz melanomas, mucosal melanomas, and uveal melanomas. The general term
is proposed to encompass "intermediate" tumors that have an increased (though still low) probability of disease progression to melanoma.
Melanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogen-activated ...protein (MAP) kinase pathway commonly mutated in melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS.
We analyzed array comparative genomic hybridization data from 102 primary melanomas (38 from mucosa, 28 from acral skin, and 18 from skin with and 18 from skin without chronic sun-induced damage) for DNA copy number aberrations specific to melanoma subtypes where mutations in BRAF and NRAS are infrequent. A narrow amplification on 4q12 was found, and candidate genes within it were analyzed.
Oncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary melanomas found mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels.
KIT is an important oncogene in melanoma. Because the majority of the KIT mutations we found in melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global melanoma burden.
Genetic analysis of melanomas from 37 patients sampled in 150 different areas showed that
BRAF
mutations were present from the first stages of tumor development, and progressively more malignant ...lesions showed acquisition of abnormalities in a predictable sequence.
Cancer arises through the accumulation of genetic alterations that lead to unrestrained cell proliferation. Large-scale sequencing projects that catalogue mutations in melanoma have been carried out mostly on advanced tumors, so it is difficult to infer the order of mutations. Melanomas often arise from distinctive precursor lesions such as melanocytic nevi, intermediate lesions, or melanoma in situ, which makes the analysis of their progression possible.
The succession of genetic alterations that leads to melanoma is incompletely understood. Somatic mutations in dominant melanoma oncogenes such as
BRAF
,
NRAS
,
GNAQ
, or
GNA11
and rearrangements resulting in fusion kinases are . . .
Uveal melanoma (UM) is the most common cancer in adult eyes. Approximately 80% of UMs harbor somatic activating mutations in GNAQ or GNA11 (encoding Gq or G11, respectively). Herein, we show in both ...cell culture and human tumors that cancer-associated Gq/11 mutants activate YAP, a major effector of the Hippo tumor suppressor pathway that is also regulated by G protein-coupled receptor signaling. YAP mediates the oncogenic activity of mutant Gq/11 in UM development, and the YAP inhibitor verteporfin blocks tumor growth of UM cells containing Gq/11 mutations. This study reveals an essential role of the Hippo-YAP pathway in Gq/11-induced tumorigenesis and suggests YAP as a potential drug target for UM patients carrying mutations in GNAQ or GNA11.
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•Uveal melanoma-associated mutant Gq/11 activates YAP•YAP activation correlates with mutations of Gq/11 in uveal melanomas•YAP is essential for mutant Gq/11-induced uveal melanoma growth•YAP inhibitor suppresses mutant Gq/11-induced uveal melanoma development
Yu et al. show that uveal melanomas with GNAQ- or GNA11-activating mutations have constitutively active YAP. These tumors, but not those driven by mutant BRAF, can be suppressed by YAP inhibition, suggesting YAP as a potential therapeutic target in these tumors.
Uveal melanoma (UM) is a currently untreatable form of melanoma with a 50% mortality rate. Characterization of the essential signaling pathways driving this cancer is critical to develop target ...therapies. Activating mutations in the Gαq signaling pathway at the level of GNAQ, GNA11, or rarely CYSLTR2 or PLCβ4 are considered alterations driving proliferation in UM and several other neoplastic disorders. Here, we systematically examined the oncogenic signaling output of various mutations recurrently identified in human tumors. We demonstrate that CYSLTR2 → GNAQ/11 → PLCβ act in a linear signaling cascade that, via protein kinase C (PKC), activates in parallel the MAP-kinase and FAK/Yes-associated protein pathways. Using genetic ablation and pharmacological inhibition, we show that the PKC/RasGRP3/MAPK signaling branch is the essential component that drives the proliferation of UM. Only inhibition of the MAPK branch but not the FAK branch synergizes with inhibition of the proximal cascade, providing a blueprint for combination therapy. All oncogenic signaling could be extinguished by the novel GNAQ/11 inhibitor YM-254890, in all UM cells with driver mutation in the Gαq subunit or the upstream receptor. Our findings highlight the GNAQ/11 → PLCβ → PKC → MAPK pathway as the central signaling axis to be suppressed pharmacologically to treat for neoplastic disorders with Gαq pathway mutations.
Common acquired melanocytic nevi are benign neoplasms that are composed of small, uniform melanocytes and are typically present as flat or slightly elevated pigmented lesions on the skin. We describe ...two families with a new autosomal dominant syndrome characterized by multiple, skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected individuals developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of BAP1, which encodes a ubiquitin carboxy-terminal hydrolase. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histological similarities to the familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.
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