Dataset Information

Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.

ABSTRACT: Spitzoid neoplasms are a group of melanocytic tumours with distinctive histopathological features. They include benign tumours (Spitz naevi), malignant tumours (spitzoid melanomas) and tumours with borderline histopathological features and uncertain clinical outcome (atypical Spitz tumours). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbour kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%) and RET (3%) in a mutually exclusive pattern. The chimeric proteins are constitutively active, stimulate oncogenic signalling pathways, are tumourigenic and are found in the entire biologic spectrum of spitzoid neoplasms, including 55% of Spitz naevi, 56% of atypical Spitz tumours and 39% of spitzoid melanomas. Kinase inhibitors suppress the oncogenic signalling of the fusion proteins in vitro. In summary, kinase fusions account for the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanomas.

SUBMITTER: Wiesner T

PROVIDER: S-EPMC4084638 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.

Wiesner Thomas T He Jie J Yelensky Roman R Esteve-Puig Rosaura R Botton Thomas T Yeh Iwei I Lipson Doron D Otto Geoff G Brennan Kristina K Murali Rajmohan R Garrido Maria M Miller Vincent A VA Ross Jeffrey S JS Berger Michael F MF Sparatta Alyssa A Palmedo Gabriele G Cerroni Lorenzo L Busam Klaus J KJ Kutzner Heinz H Cronin Maureen T MT Stephens Philip J PJ Bastian Boris C BC

Nature communications 20140101

Spitzoid neoplasms are a group of melanocytic tumours with distinctive histopathological features. They include benign tumours (Spitz naevi), malignant tumours (spitzoid melanomas) and tumours with borderline histopathological features and uncertain clinical outcome (atypical Spitz tumours). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbour kinase fusions of ROS1 (17%), NTR ...[more]

PMID: 24445538

Similar Datasets

Project description:Melanomas that have histopathologic features that overlap with those of Spitz nevus are referred to as spitzoid melanomas. However, the diagnostic concept is used inconsistently and genomic analyses suggest it is a heterogeneous category. Spitz tumors, the spectrum of melanocytic neoplasms extending from Spitz nevi to their malignant counterpart Spitz melanoma, are defined in the 2018 WHO classification of skin tumors by the presence of specific genetic alterations, such as kinase fusions or HRAS mutations. It is unclear what fraction of "spitzoid melanomas" defined solely by their histopathologic features belong to the category of Spitz melanoma or to other melanoma subtypes. We assembled a cohort of 25 spitzoid melanomas diagnosed at a single institution over an 8-year period and performed high-coverage DNA sequencing of 480 cancer related genes. Transcriptome wide RNA sequencing was performed for select cases. Only nine cases (36%) had genetic alterations characteristic of Spitz melanoma, including HRAS mutation or fusion involving BRAF, ALK, NTRK1, or MAP3K8. The remaining cases were divided into those with an MAPK activating mutation and those without an MAPK activating mutation. Both Spitz melanoma and spitzoid melanomas in which an MAPK-activating mutation could not be identified tended to occur in younger patients on skin with little solar elastosis, infrequently harbored TERT promoter mutations, and had a lower burden of pathogenic mutations than spitzoid melanomas with non-Spitz MAPK-activating mutations. The MAPK-activating mutations identified affected non-V600 residues of BRAF as well as NRAS, MAP2K1/2, NF1, and KIT, while BRAF V600 mutations, the most common mutations in melanomas of the WHO low-CSD category, were entirely absent. While the "spitzoid melanomas" comprising our cohort were enriched for bona fide Spitz melanomas, the majority of melanomas fell outside of the genetically defined category of Spitz melanomas, indicating that histomorphology is an unreliable predictor of Spitz lineage.

Project description:A subset of melanomas is characterized by fusions involving genes that encode kinases. Melanomas with RAF1 fusions have been rarely reported, mostly in clinical literature. To investigate this distinctive group of melanomas, we searched for melanomas with activating structural variants in RAF1, utilizing our case archive of clinical samples with comprehensive genomic profiling (CGP) by a hybrid capture-based DNA sequencing platform. Clinical data, pathology reports, and histopathology were reviewed for each case. RAF1 breakpoints, fusion partners, and co-occurring genetic alterations were characterized. From a cohort of 7119 melanomas, 40 cases (0.6%) featured fusions that created activating structural variants in RAF1. Cases with activating RAF1 fusions had median age of 62 years, were 58% male, and consisted of 9 primary tumors and 31 metastases. Thirty-nine cases were cutaneous primary, while one case was mucosal (anal) primary. Primary cutaneous melanomas showed variable architectures, including wedge-shaped and nodular growth patterns. Cytomorphology was predominantly epithelioid, with only one case, a desmoplastic melanoma, consisting predominantly of spindle cells. RAF1 5' rearrangement partners were predominantly intrachromosomal (n = 18), and recurrent partners included MAP4 (n = 3), CTNNA1 (n = 2), LRCH3 (n = 2), GOLGA4 (n = 2), CTDSPL (n = 2), and PRKAR2A (n = 2), all 5' of the region encoding the kinase domain. RAF1 breakpoints occurred in intron 7 (n = 32), intron 9 (n = 4), intron 5 (n = 2), and intron 6 (n = 2). Ninety-eight percent (n = 39) were wild type for BRAF, NRAS, and NF1 genomic alterations (triple wild type). Activating RAF1 fusions were present in 2.1% of triple wild-type melanomas overall (39/1882). In melanomas with activating RAF1 fusions, frequently mutated genes included TERTp (62%), CDKN2A (60%), TP53 (13%), ARID2 (10%), and PTEN (10%). Activating RAF1 fusions characterize a significant subset of triple wild-type melanoma (2.1%) with frequent accompanying mutations in TERTp and CDKN2A. CGP of melanomas may improve tumor classification and inform potential therapeutic options, such as consideration of specific kinase inhibitors.

Project description:Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas common acquired naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion and may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are usually capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour progression will refine the classification of spitzoid melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy.

Dataset Information

Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.

Publications

Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets