Distinct Pathways in the Pathogenesis of Sebaceous Carcinomas Implicated by Differentially Expressed MicroRNAs

Tetzlaff, Michael T.; Curry, Jonathan L.; Yin, Vivian T.; Pattanaprichakul, Penvadee; Manonukul, Jane; Uiprasertkul, Mongkol; Manyam, Ganiraju C.; Wani, Khalida; Aldape, Kenneth; Zhang, Li; Prieto, Víctor G.; Esmaeli, Bita

doi:10.1001/jamaophthalmol.2015.2310

Cited by 35 publications

(24 citation statements)

References 48 publications

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“…In particular, among primary and metastatic ocular SCs, we identified mutations in PTEN (two lesions from two patients), PIK3CA (five lesions from two patients), ERBB2 (four lesions from one patient), NF1 (one lesion), AKT (one lesion), and BRAF (one lesion) – all of which are predicted to impact the phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K) signalling cascade (Figure A and supplementary material, Table S2). Both miR‐486‐5p and miR‐1 are also up‐regulated in ocular SC , and these specifically target components in the PI3K pathway . Together, this constellation of changes implicates PI3K pathway activation as being central to ocular sebaceous carcinomagenesis.…”

Section: Resultsmentioning

confidence: 91%

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Next‐generation sequencing identifies high frequency of mutations in potentially clinically actionable genes in sebaceous carcinoma

Tetzlaff

Singh

Seviour

et al. 2016

The Journal of Pathology

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Sebaceous carcinoma (SC) is a rare but aggressive malignancy with frequent recurrence and metastases. Surgery is the mainstay of therapy, but effective systemic therapies are lacking because the molecular alterations driving SC remain poorly understood. To identify these, we performed whole-exome next-generation sequencing of 409 cancer-associated genes on 27 SCs (18 primary/locally recurrent ocular, 5 paired metastatic ocular, and 4 primary extraocular) from 20 patients. In ocular SC, we identified 139 non-synonymous somatic mutations (median/lesion 3; range 0-23). Twenty-five of 139 mutations (18%) occurred in potentially clinically actionable genes in 6 of 16 patients. The most common mutations were mutations in TP53 (n = 9), RB1 (n = 6), PIK3CA (n = 2), PTEN (n = 2), ERBB2 (n = 2), and NF1 (n = 2). TP53 and RB1 mutations were restricted to ocular SC and correlated with aberrant TP53 and RB protein expression. Systematic pathway analyses demonstrated convergence of these mutations to activation of the PI3K signalling cascade, and PI3K pathway activation was confirmed in tumours with PTEN and/or PIK3CA mutations. Considerable inter-tumoural heterogeneity was observed between paired primary and metastatic ocular SCs. In primary extraocular SC, we identified 77 non-synonymous somatic mutations (median/lesion 22.5; range 3-29). This overall higher mutational load was attributed to a microsatellite instability phenotype in three of four patients and somatically acquired mutations in mismatch repair genes in two of four patients. Eighteen of 77 mutations (23%) were in potentially clinically actionable genes in three of four patients, including BTK, FGFR2, PDGFRB, HRAS, and NF1 mutations. Identification of potentially clinically actionable mutations in 9 of 20 SC patients (45%) underscores the importance of next-generation sequencing to expand the spectrum of genotype-matched targeted therapies. Frequent activation of PI3K signalling pathways provides a strong rationale for application of mTOR inhibitors in the management of this disease. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Resultsmentioning

confidence: 91%

“…Connecting nodes were added using the gene connector function. Differentially expressed miRNAs in primary ocular SC were identified previously . Where available, miRNA–mRNA interaction data were downloaded from the starBase Ago‐CLIP‐Seq database (http://starbase.sysu.edu.cn).…”

Section: Methodsmentioning

confidence: 99%

Next‐generation sequencing identifies high frequency of mutations in potentially clinically actionable genes in sebaceous carcinoma

Tetzlaff

Singh

Seviour

et al. 2016

The Journal of Pathology

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“…Finally, few studies have been performed at the RNA level and although some novel aberrant miRNAs and IncRNAs have been suggested to play a role this landscape is yet to be fully explored . Large scale molecular studies will help to elucidate the role of germline and somatic variations in the disease pathogenesis.…”

Section: Genetic and Molecular Pathology Findings In Sebaceous Tumoursmentioning

confidence: 99%

“…The reliable separation of sebaceoma from its malignant counterpart sebaceous carcinoma remains particularly problematic, especially on partial samples . Over the past few years our understanding of the molecular pathways and genetic events involved in the pathogenesis of sebaceous tumours, especially sebaceous carcinomas, has evolved significantly …”

Section: Introductionmentioning

confidence: 99%

Update on the pathology, genetics and somatic landscape of sebaceous tumours

et al. 2020

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Cutaneous sebaceous neoplasms show a predilection for the head and neck area of adults and include tumours with benign behaviour, sebaceous adenoma and sebaceoma, and sebaceous carcinoma with potential for an aggressive disease course at the malignant end of the spectrum. The majority of tumours are solitary and sporadic, but a subset of tumours may be associated with Lynch syndrome, also known as hereditary non‐polyposis colon cancer (HNPCC) and previously referred to as Muir‐Torre syndrome (now known to be part of Lynch syndrome). This review provides an overview of the clinical and histological features of cutaneous sebaceous neoplasia with an emphasis on differentiating features and differential diagnosis. It also offers insights into the recently described molecular pathways involved in the development of sebaceous tumours and their association with Lynch syndrome.

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“…One approach is to macrodissect regions containing apparently homogenous populations of the cell type of interest based on histopathological evaluation of H&E stained slides [77]. A second approach adopted in multiple studies is to use laser capture microdissection to isolate cells of interest [69,78] Additionally, flow cytometry has been successfully used to select specific cell subtypes, such as epithelial cells, in samples of dissociated, intact cells [76].…”

Section: Selected Cell Populations Of Interestmentioning

confidence: 99%

Variability in, variability out: best practice recommendations to standardize pre-analytical variables in the detection of circulating and tissue microRNAs

Khan

Lieberman

Lockwood

2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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microRNAs (miRNAs) hold promise as biomarkers for a variety of disease processes and for determining cell differentiation. These short RNA species are robust, survive harsh treatment and storage conditions and may be extracted from blood and tissue. Pre-analytical variables are critical confounders in the analysis of miRNAs: we elucidate these and identify best practices for minimizing sample variation in blood and tissue specimens. Preanalytical variables addressed include patient-intrinsic variation, time and temperature from sample collection to storage or processing, processing methods, contamination by cells and blood components, RNA extraction method, normalization, and storage time/conditions. For circulating miRNAs, hemolysis and blood cell contamination significantly affect profiles; samples should be processed within 2 h of collection; ethylene diamine tetraacetic acid (EDTA) is preferred while heparin should be avoided; samples should be "double spun" or filtered; room temperature or 4 °C storage for up to 24 h is preferred; miRNAs are stable for at least 1 year at -20 °C or -80 °C. For tissuebased analysis, warm ischemic time should be < 1 h; cold ischemic time (4 °C) < 24 h; common fixative used for all specimens; formalin fix up to 72 h prior to processing; enrich for cells of interest; validate candidate biomarkers with in situ visualization. Most importantly, all specimen types should have standard and common workflows with careful documentation of relevant pre-analytical variables.

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Distinct Pathways in the Pathogenesis of Sebaceous Carcinomas Implicated by Differentially Expressed MicroRNAs

Cited by 35 publications

References 48 publications

Next‐generation sequencing identifies high frequency of mutations in potentially clinically actionable genes in sebaceous carcinoma

Next‐generation sequencing identifies high frequency of mutations in potentially clinically actionable genes in sebaceous carcinoma

Update on the pathology, genetics and somatic landscape of sebaceous tumours

Variability in, variability out: best practice recommendations to standardize pre-analytical variables in the detection of circulating and tissue microRNAs

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