Dataset Information

Novel MIR143-NOTCH fusions in benign and malignant glomus tumors.

ABSTRACT: Glomus tumors (GT) have been classified among tumors of perivascular smooth muscle differentiation, together with myopericytoma, myofibroma/tosis, and angioleiomyoma, based on their morphologic overlap. However, no molecular studies have been carried out to date to investigate their genetic phenotype and to confirm their shared pathogenesis. RNA sequencing was performed in three index cases (GT1, malignant GT; GT2, benign GT and M1, multifocal myopericytoma), followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired-end RNA-seq data. A gene fusion involving MIR143 in band 5q32 was identified in both GTs with either NOTCH2 in 1p13 in GT1 or NOTCH1 in 9q34 in GT2, but none in M1. After being validated by FISH and RT-PCR, these abnormalities were screened on 33 GTs, 6 myopericytomas, 9 myofibroma/toses, 18 angioleiomyomas and in a control group of 5 sino-nasal hemangiopericytomas. Overall NOTCH2 gene rearrangements were identified in 52% of GT, including all malignant cases and one NF1-related GT. No additional cases showed NOTCH1 rearrangement. As NOTCH3 shares similar functions with NOTCH2 in regulating vascular smooth muscle development, the study group was also investigated for abnormalities in this gene by FISH. Indeed, NOTCH3 rearrangements were identified in 9% of GTs, all present in benign soft tissue GT, one case being fused to MIR143. Only 1/18 angioleiomyomas showed NOTCH2 gene rearrangement, while all the myopericytomas and myofibroma/toses were negative. In summary, we describe novel NOTCH1-3 rearrangements in benign and malignant, visceral, and soft tissue GTs.

SUBMITTER: Mosquera JM

PROVIDER: S-EPMC3889711 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Novel MIR143-NOTCH fusions in benign and malignant glomus tumors.

Mosquera Juan-Miguel JM Sboner Andrea A Zhang Lei L Chen Chun-Liang CL Sung Yun-Shao YS Chen Hsiao-Wei HW Agaram Narasimhan P NP Briskin Daniel D Basha Basma M BM Singer Samuel S Rubin Mark A MA Tuschl Thomas T Antonescu Cristina R CR

Genes, chromosomes & cancer 20130902 11

Glomus tumors (GT) have been classified among tumors of perivascular smooth muscle differentiation, together with myopericytoma, myofibroma/tosis, and angioleiomyoma, based on their morphologic overlap. However, no molecular studies have been carried out to date to investigate their genetic phenotype and to confirm their shared pathogenesis. RNA sequencing was performed in three index cases (GT1, malignant GT; GT2, benign GT and M1, multifocal myopericytoma), followed by FusionSeq data analysis, ...[more]

PMID: 23999936

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Project description:BackgroundMalignant glomus tumors are exceedingly rare, however they can be locally aggressive and have the potential to metastasize. There is limited information available in the literature regarding treatment and outcomes, therefore we present a case series of 5 patients with glomus tumors with malignant features confined to the extremities that have presented to our tertiary sarcoma center within the last 20 years. This is the largest case series of its kind in the malignant glomus tumor literature, to our knowledge.MethodsWe performed a retrospective chart review of all patients with histologically confirmed glomus tumors with malignant features in the extremities found within the University of Michigan EMERSE database since January 1st, 2000.ResultsFive patients met our inclusion and exclusion criteria. Three patients were diagnosed with malignant glomus tumors, one patient with glomus tumor with uncertain malignant potential, and the last patient with malignant glomus tumor with leiomyosarcomatous features. Males and females were equally represented. Age range was 9-49 years at time of first presentation. All patients underwent an initial surgical resection. Three of the five patients (60%) underwent initial resection at an outside hospital prior to referral to tertiary sarcoma center, and all three required re-resection. One of these patients had local tumor recurrence after a planned positive margin resection and radiotherapy. Another patient had distant metastasis after a positive margin surgical resection and a short course of radiotherapy. All patients are still alive according to their medical record with the average time from initial treatment to last follow up of 59.2 months.ConclusionsOur study supports the current literature that wide-local resection with the goal of negative margins is still the current gold standard treatment for glomus tumors with malignant features. Studies with larger cohorts are necessary before recommending for or against radiotherapy or chemotherapy. Early biopsy and referral to a tertiary sarcoma center prior to surgical resection may help reduce the re-resection rate and potential seeding of the tumor in these patients, thereby improving outcomes.

Project description:ContextFine-needle aspiration (FNA) is the best diagnostic tool for preoperative evaluation of thyroid nodules but is often inconclusive as a guide for surgical management.ObjectiveOur hypothesis was that thyroid tumor subtypes may show characteristic DNA copy number variation (CNV) patterns, which may further improve the preoperative classification.DesignOur study cohorts included benign follicular adenomas (FAs), classic papillary thyroid carcinomas (PTCs), and follicular variant PTCs (FVPTCs), the three subtypes most commonly associated with inconclusive preoperative cytopathology.SettingTissue and FNA samples were obtained at an academic tertiary referral center.PatientsCases were identified that underwent partial or complete thyroidectomy for malignant or indeterminate thyroid lesions between 2000 and 2008 and had adequate snap-frozen tissue.InterventionsPairs of tumor tissue and matching normal thyroid tissue-derived DNA were compared using 550K single-nucleotide polymorphism arrays.Main outcome measureStatistically significant differences in CNV patterns between tumor subtypes were identified.ResultsSegmental amplifications in chromosomes (Ch) 7 and 12 were more common in FAs than in PTCs or FVPTCs. Additionally, a subset of FAs and FVPTCs showed deletions in Ch22. We identified the 5 CNV-associated genes best at discriminating between FAs and PTCs/FVPTCs, which correctly classified 90% of cases. These 5 Ch12 genes were validated by quantitative genomic PCR and gene expression array analyses on the same patient cohort. The 5-gene signature was then successfully validated against an independent test cohort of benign and malignant tumor samples. Finally, we performed a feasibility study on matched FA-derived intraoperative FNA samples and were able to correctly identify FAs harboring the Ch12 amplification signature, whereas FAs without amplification showed a normal Ch12 signature.ConclusionsThyroid tumor subtypes possess characteristic genomic profiles that may further our understanding of structural genetic changes in thyroid tumor subtypes and may lead to the development of new diagnostic biomarkers in FNA samples.

Dataset Information

Novel MIR143-NOTCH fusions in benign and malignant glomus tumors.

Publications

Novel MIR143-NOTCH fusions in benign and malignant glomus tumors.

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