Epigenetic dysregulation underpins tumorigenesis in a cutaneous tumor syndrome

AbstractPatients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes 1,2. We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. Novel driver mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic and methylation profiling suggest that mutated DNMT3A drives tumorigenesis mechanistically through Wnt/ß-catenin pathway signaling. Phylogenetic and mutational signature analyses confirm the phenomenon of benign pulmonary metastases from primary skin lesions. In malignant tumors, additional epigenetic modifiers MBD4, CREBBP, KDM6A and EP300 were mutated. We thus present epigenetic dysregulation as a driver in CCS tumorigenesis and propose this may account for the diverse histophenotypic patterns despite the paucity of mutations seen. These findings add novel dimensions to existing paradigms of cutaneous tumorigenesis and metastasis.

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Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome

Nature Communications ◽

10.1038/s41467-019-12746-w ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Helen R. Davies ◽

Kirsty Hodgson ◽

Edward Schwalbe ◽

Jonathan Coxhead ◽

Naomi Sinclair ◽

...

Keyword(s):

Pulmonary Metastases ◽

Malignant Tumors ◽

Skin Tumors ◽

Benign Tumors ◽

Multigenerational Families ◽

Epigenetic Modifiers ◽

Genomic Landscape ◽

Recurrent Mutations ◽

Multi Level ◽

Genomic Methylation

Abstract Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. Here, we comprehensively profile the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families and discover recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumors suggest that isoform-specific DNMT3A2 mutations are associated with dysregulated methylation. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumors. These findings contribute to existing paradigms of cutaneous tumorigenesis and metastasis.

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HISTOPATHOLOGICAL SPECTRUM OF SKIN LESIONS: A TWO YEAR RETROSPECTIVE STUDY.

10.36106/ijsr/6201091 ◽

2021 ◽

pp. 26-29

Author(s):

Shruti Shemawat ◽

Sakshi Apurva ◽

D.P Soni ◽

Saurabh Soni

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Relative Frequency ◽

Malignant Tumors ◽

Skin Lesions ◽

Benign Tumors ◽

Histopathological Diagnosis ◽

Neoplastic Lesions ◽

Skin Biopsies ◽

Age And Sex

INTRODUCTION: The skin being largest organ of the body has vast spectrum of disorders which can be difcult to diagnose correctly solely on the basis of clinical features. Hence histopathological examination is necessary to categorise skin lesions. The aim was to study relative frequency of various skin lesions and distribution of these lesions according to age and sex. METHODS: This is a retrospective descriptive hospital based study. The skin biopsies samples which came in the duration of two years from January 2019 to December 2020 at the Department of Pathology, Sardar Patel Medical college and associated group of hospitals, Bikaner, Rajasthan were taken in this study. All skin biopsies that showed denite histopathological diagnosis were included. After proper xing and staining procedures these lesions were examined under light microscopy and categorized as non-neoplastic and neoplastic. Relative frequency of various lesions, distribution of lesions according to age and sex was analyzed. The data collected was tabulated, interpreted and compared with other similar studies. RESULTS: Out of 346 patients, incidence of neoplastic lesions 259 (74.9%) were higher than non-neoplastic lesions 87(25.1%). Males were affected more compared to females with male to female ratio 1.45:1. Non-neoplastic lesions were mostly caused because of infectious etiologies among which leprosy was the most common infection. Keratinocytic tumors 99(52.2%) constituted most common type of neoplastic lesion. Benign tumors 191(73.7%) outnumbered malignant tumors 68(26.3%). The cases of benign tumors were seen more in younger population while that of malignant tumors were seen in older age groups. Among the keratinocytic type of malignant skin tumors squamous cell carcinoma (63.5%) was the most common variant which was followed by basal cell carcinoma 19(36.5%). Male predominance was observed in both squamous cell carcinoma and basal cell carcinoma. CONCLUSION: A wide heterogenesity of skin lesions was observed in the present study . These skin lesions were mostly affecting age group of 10-30 years. Inspite of extensive programmes and research, leprosy and tuberculosis remains a rampant cause of infectious non-neoplastic skin lesions. Sometimes ignorance by patient for a very small appearing skin lesions becomes life threatening. Hence early clinician consultation with proper examination and accurate histopathological diagnosis becomes the mainstay in early treatment and recovery.

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The Development of a Skin Cancer Classification System for Pigmented Skin Lesions Using Deep Learning

Biomolecules ◽

10.3390/biom10081123 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1123 ◽

Cited By ~ 2

Author(s):

Shunichi Jinnai ◽

Naoya Yamazaki ◽

Yuichiro Hirano ◽

Yohei Sugawara ◽

Yuichiro Ohe ◽

...

Keyword(s):

Skin Cancer ◽

Malignant Tumors ◽

Skin Lesions ◽

Training Dataset ◽

Clinical Image ◽

Benign Tumors ◽

Clinical Images ◽

Predictive Values ◽

Test Dataset ◽

Pigmented Skin Lesions

Recent studies have demonstrated the usefulness of convolutional neural networks (CNNs) to classify images of melanoma, with accuracies comparable to those achieved by dermatologists. However, the performance of a CNN trained with only clinical images of a pigmented skin lesion in a clinical image classification task, in competition with dermatologists, has not been reported to date. In this study, we extracted 5846 clinical images of pigmented skin lesions from 3551 patients. Pigmented skin lesions included malignant tumors (malignant melanoma and basal cell carcinoma) and benign tumors (nevus, seborrhoeic keratosis, senile lentigo, and hematoma/hemangioma). We created the test dataset by randomly selecting 666 patients out of them and picking one image per patient, and created the training dataset by giving bounding-box annotations to the rest of the images (4732 images, 2885 patients). Subsequently, we trained a faster, region-based CNN (FRCNN) with the training dataset and checked the performance of the model on the test dataset. In addition, ten board-certified dermatologists (BCDs) and ten dermatologic trainees (TRNs) took the same tests, and we compared their diagnostic accuracy with FRCNN. For six-class classification, the accuracy of FRCNN was 86.2%, and that of the BCDs and TRNs was 79.5% (p = 0.0081) and 75.1% (p < 0.00001), respectively. For two-class classification (benign or malignant), the accuracy, sensitivity, and specificity were 91.5%, 83.3%, and 94.5% by FRCNN; 86.6%, 86.3%, and 86.6% by BCD; and 85.3%, 83.5%, and 85.9% by TRN, respectively. False positive rates and positive predictive values were 5.5% and 84.7% by FRCNN, 13.4% and 70.5% by BCD, and 14.1% and 68.5% by TRN, respectively. We compared the classification performance of FRCNN with 20 dermatologists. As a result, the classification accuracy of FRCNN was better than that of the dermatologists. In the future, we plan to implement this system in society and have it used by the general public, in order to improve the prognosis of skin cancer.

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Retrospective study on parotid gland tumors

ORL ro ◽

10.26416/orl.33.4.2016.155 ◽

2016 ◽

Vol 4 (1) ◽

pp. 22-23

Author(s):

Ibric Cioranu ◽

Vlad Petrescu Seceleanu ◽

Viorel Ibric Cioranu ◽

Andreea Smarandache ◽

Sorin Vasilescu ◽

...

Keyword(s):

Malignant Tumors ◽

Maxillofacial Surgery ◽

Squamous Carcinoma ◽

Benign Tumors ◽

Warthin Tumor ◽

Parotid Tumors ◽

Non Hodgkin Lymphoma ◽

Adenoid Cystic ◽

Modal Treatment ◽

Surgery Department

During 2011-2012, 56 patients diagnosed with parotid tumors were admitted to the Maxillofacial Surgery Department of “Lucian Blaga” University and in Euroclinic Hospital. 72% were benign tumors and 28% malignant. All patients received surgical treatment (total or partial parotidectomy). For the malignant tumors, radiotherapy was added to the modal treatment (94% of the cases). Pleomorphic adenoma was encountered in 70% of the benign cases, followed by Warthin tumor in 15%. Adenoid cystic carcinoma was noticed in 31% of the malignant cases, mucoepidermoid carcinoma in 25% of the cases, and squamous carcinoma and non-Hodgkin lymphoma on 12.5% of the malignant cases.

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Multimodality imaging review of focal renal lesions

Egyptian Journal of Radiology and Nuclear Medicine ◽

10.1186/s43055-020-00391-z ◽

2021 ◽

Vol 52 (1) ◽

Author(s):

Jonathan Lyske ◽

Rishi Philip Mathew ◽

Christopher Hutchinson ◽

Vimal Patel ◽

Gavin Low

Keyword(s):

Malignant Tumors ◽

Multimodality Imaging ◽

Lymphoproliferative Disease ◽

Benign Tumors ◽

Main Body ◽

Imaging Features ◽

Focal Lesions ◽

Renal Lesions ◽

Positron Emission ◽

Neoplastic Lesions

Abstract Background Focal lesions of the kidney comprise a spectrum of entities that can be broadly classified as malignant tumors, benign tumors, and non-neoplastic lesions. Malignant tumors include renal cell carcinoma subtypes, urothelial carcinoma, lymphoma, post-transplant lymphoproliferative disease, metastases to the kidney, and rare malignant lesions. Benign tumors include angiomyolipoma (fat-rich and fat-poor) and oncocytoma. Non-neoplastic lesions include infective, inflammatory, and vascular entities. Anatomical variants can also mimic focal masses. Main body of the abstract A range of imaging modalities are available to facilitate characterization; ultrasound (US), contrast-enhanced ultrasound (CEUS), computed tomography (CT), magnetic resonance (MR) imaging, and positron emission tomography (PET), each with their own strengths and limitations. Renal lesions are being detected with increasing frequency due to escalating imaging volumes. Accurate diagnosis is central to guiding clinical management and determining prognosis. Certain lesions require intervention, whereas others may be managed conservatively or deemed clinically insignificant. Challenging cases often benefit from a multimodality imaging approach combining the morphology, enhancement and metabolic features. Short conclusion Knowledge of the relevant clinical details and key imaging features is crucial for accurate characterization and differentiation of renal lesions.

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PTEN Hamartoma Tumor Syndrome/Cowden Syndrome: Genomics, Oncogenesis, and Imaging Review for Associated Lesions and Malignancy

Cancers ◽

10.3390/cancers13133120 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3120

Author(s):

David D. Dragoo ◽

Ahmed Taher ◽

Vincenzo K. Wong ◽

Ahmed Elsaiey ◽

Nikita Consul ◽

...

Keyword(s):

Autosomal Dominant ◽

Malignant Tumors ◽

Cowden Syndrome ◽

Benign Tumors ◽

Imaging Findings ◽

Pten Hamartoma Tumor Syndrome ◽

Associated Lesions ◽

Tumor Recognition ◽

Integral Role ◽

Early Tumor

PTEN hamartoma tumor syndrome/Cowden syndrome (CS) is a rare autosomal dominant syndrome containing a germline PTEN mutation that leads to the development of multisystem hamartomas and oncogenesis. Benign tumors such as Lhermitte–Duclos disease and malignant tumors involving the breast, thyroid, kidneys, and uterus are seen in CS. Radiologists have an integral role in the comanagement of CS patients. We present the associated imaging findings and imaging screening recommendations. Knowledge of the types of cancers commonly seen in CS and their imaging findings can aid in early tumor recognition during cancer screening to help ensure near-normal life spans in CS patients.

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Role of CA 19-9 in complex ovarian tumors

10.1055/s-0039-1685299 ◽

2016 ◽

Author(s):

Dhanya S. Thomas ◽

Ajit Sebastian ◽

Vinotha Thomas ◽

Anitha Thomas ◽

Rachel Chandy ◽

...

Keyword(s):

Malignant Tumors ◽

Ovarian Tumors ◽

Benign Tumors ◽

Ovarian Mass ◽

Radiological Findings ◽

Epithelial Tumors ◽

Mucin Glycoprotein ◽

Glycoprotein Antigen ◽

Mucinous Tumours

Background: Cancer antigen 19-9 (CA 19-9) is a tumor-associated mucin glycoprotein antigen that may be elevated in healthy individuals as well as in patients with benign and malignant tumors. It is useful in the management of pancreatic and other gastrointestinal tumors. CA 19-9 is also elevated in benign and malignant ovarian tumors. Aim: To study the pattern of serum CA19-9 in complex ovarian tumors. Methods: The study design was descriptive, based on data collected from medical records. Patients with a complex ovarian mass, who were investigated with CA 19-9 and had undergone surgery, wereincluded in the study. The study duration was 2 years from January 2014 to December 2015. A total of 273 patients (119 - benign and 154 malignant) with complex ovarian mass and elevated CA 19-9 underwent surgery during the study period. Results: CA 19-9 was elevated in 55 patients (20%). Of these, 23 patients had benign tumors while 32 had malignant tumors.Among patients with benign tumors, 21 had dermoid, 23 had mucinous tumors and 75 had other types of tumors. CA 19-9 was elevated in 10 (47.6%) of the dermoids, 7 (30.4%) of the mucinous tumors and 6 (8%) of the other benign tumors. Among patients with malignant tumors, 138 were epithelial and 16 were non epithelial tumors. Of the epithelial tumors, 31 were mucinous and 107 were non mucinous types. Overall, 29 (21%) had elevated CA 19-9. Of the epithelial tumors, 22.6% of the mucinous type and 20.6% of the non mucinous type had elevated CA 19-9. Among the non-epithelial tumors, 3 (18.8%) had elevated CA19-9. Conclusion: CA 19-9 is elevated in several conditions but most likely to be raised in dermoid cysts and mucinous tumours. CA19-9 levels need to be interpreted along with clinical and radiological findings.

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Risk of Metastatic Ovarian Involvement in Nongynecologic Malignancies

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e3182332cd1 ◽

2012 ◽

Vol 22 (1) ◽

pp. 3-8 ◽

Cited By ~ 4

Author(s):

Kidong Kim ◽

Soo Youn Cho ◽

Sang-Il Park ◽

Hye Jin Kang ◽

Beob-Jong Kim ◽

...

Keyword(s):

Overall Survival ◽

Malignant Tumors ◽

Rank Test ◽

Benign Tumors ◽

Binary Logistic Regression Analysis ◽

Fisher Exact Test ◽

Tumor Type ◽

Metastatic Tumors ◽

Number Of Patients ◽

Adnexal Tumors

ObjectiveThe objectives were to evaluate the risk of malignant adnexal tumors in women with nongynecologic malignancies and to identify variables associated with the risk of malignant adnexal tumors.MethodsThe eligibility criteria included the diagnosis of a nongynecologic malignancy and adnexal tumors, which were resected or subjected to biopsy at our institute between 1999 and 2010. The risk of malignant adnexal tumors was assessed by dividing the number of patients with metastatic tumors to the adnexa or primary adnexal cancers by the total number of patients. The association of clinicopathologic variables with the risk of malignant adnexal tumors was evaluated using the Fisher exact test and binary logistic regression analysis. In patients with metastatic tumors to the adnexa, the association of clinicopathologic variables with overall survival after adnexal surgery was examined using the log-rank test.ResultsIn 166 patients with adnexal tumors, 41 benign tumors, 113 metastatic tumors to the adnexa, and 12 primary adnexal cancers were diagnosed. Age older than 46 years, a tumor type associated with a high risk for malignant adnexal tumors, and bilateral tumors significantly increased the risk of malignant adnexal tumors. The overall survival of the patients with stomach cancer was significantly worse than the patients with colorectal or breast cancers.ConclusionOne hundred twenty-five of the 166 patients with nongynecologic malignancies who had adnexal tumors managed surgically were shown to have malignant tumors, and most of the tumors were metastatic from primary sites. The risk of malignant adnexal tumors was associated with age, nongynecologic malignancy, and bilaterality.

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A novel decision tree model based on chromosome imbalances in cell-free DNA and CA-125 in the differential diagnosis of ovarian cancer

The International Journal of Biological Markers ◽

10.1177/1724600821992356 ◽

2021 ◽

pp. 172460082199235

Author(s):

Weina Zhang ◽

Yu-min Zhang ◽

Yuan Gao ◽

Shengmiao Zhang ◽

Weixin Chu ◽

...

Keyword(s):

Ovarian Cancer ◽

Differential Diagnosis ◽

Decision Tree ◽

Copy Number ◽

Malignant Tumors ◽

Copy Number Variations ◽

Ca 125 ◽

Benign Tumors ◽

Cell Free Dna ◽

Free Dna

Objective: CA-125 is widely used as biomarker of ovarian cancer. However, CA-125 suffers low accuracy. We developed a hybrid analytical model, the Ovarian Cancer Decision Tree (OCDT), employing a two-layer decision tree, which considers genetic alteration information from cell-free DNA along with CA-125 value to distinguish malignant tumors from benign tumors. Methods: We consider major copy number alterations at whole chromosome and chromosome-arm level as the main feature of our detection model. Fifty-eight patients diagnosed with malignant tumors, 66 with borderline tumors, and 10 with benign tumors were enrolled. Results: Genetic analysis revealed significant arm-level imbalances in most malignant tumors, especially in high-grade serous cancers in which 12 chromosome arms with significant aneuploidy ( P<0.01) were identified, including 7 arms with significant gains and 5 with significant losses. The area under receiver operating characteristic curve (AUC) was 0.8985 for copy number variations analysis, compared to 0.8751 of CA125. The OCDT was generated with a cancerous score (CScore) threshold of 5.18 for the first level, and a CA-125 value of 103.1 for the second level. Our most optimized OCDT model achieved an AUC of 0.975. Conclusions: The results suggested that genetic variations extracted from cfDNA can be combined with CA-125, and together improved the differential diagnosis of malignant from benign ovarian tumors. The model would aid in the pre-operative assessment of women with adnexal masses. Future clinical trials need to be conducted to further evaluate the value of CScore in clinical settings and search for the optimal threshold for malignancy detection.

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