scholarly journals Braf mutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium

Gut ◽  
2021 ◽  
pp. gutjnl-2020-322166
Author(s):  
Lochlan Fennell ◽  
Alexandra Kane ◽  
Cheng Liu ◽  
Diane McKeone ◽  
Gunter Hartel ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Colorectal Neoplasia ◽  
Young Patients ◽  
Neoplastic Transformation ◽  
The Elderly ◽  
Colorectal Carcinogenesis ◽  
Neoplastic Progression ◽  
Molecular Alterations ◽  
Serrated Lesions ◽  
Aberrant Dna Methylation

ObjectiveSessile serrated lesions (SSLs) are common across the age spectrum, but the BRAF mutant cancers arising occur predominantly in the elderly. Aberrant DNA methylation is uncommon in SSL from young patients. Here, we interrogate the role of ageing and DNA methylation in SSL initiation and progression.DesignWe used an inducible model of Braf mutation to direct recombination of the oncogenic Braf V637E allele to the murine intestine. BRAF mutation was activated after periods of ageing, and tissue was assessed for histological, DNA methylation and gene expression changes thereafter. We also investigated DNA methylation alterations in human SSLs.ResultsInducing Braf mutation in aged mice was associated with a 10-fold relative risk of serrated lesions compared with young mice. There were extensive differences in age-associated DNA methylation between animals induced at 9 months versus wean, with relatively little differential Braf-specific methylation. DNA methylation at WNT pathway genes scales with age and Braf mutation accelerated age-associated DNA methylation. In human SSLs, increased epigenetic age was associated with high-risk serrated colorectal neoplasia.ConclusionsSSLs arising in the aged intestine are at a significantly higher risk of spontaneous neoplastic progression. These findings provide support for a new conceptual model for serrated colorectal carcinogenesis, whereby risk of Braf-induced neoplastic transformation is dependent on age and may be related to age-associated molecular alterations that accumulate in the ageing intestine, including DNA methylation. This may have implications for surveillance and chemopreventive strategies targeting the epigenome.

Su1359 Aberrant DNA Methylation of Colonic Serrated Lesions and Subsequent Colorectal Neoplasia in Ulcerative Colitis and Crohn's Colitis

2014 ◽  
Vol 146 (5) ◽  
pp. S-446
Author(s):  
David H. Johnson ◽  
Mohammed M. Aboelsoud ◽  
Tracy C. Yab ◽  
Xiaoming Cao ◽  
Thomas C. Smyrk ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Dna Methylation ◽  
Colorectal Neoplasia ◽  
Crohn’S Colitis ◽  
Crohn's Colitis ◽  
Serrated Lesions ◽  
Aberrant Dna Methylation

scholarly journals Cancer Diagnosis, Risk Assessment and Prediction of Therapeutic Response by Means of DNA Methylation Markers

2007 ◽  
Vol 23 (1-2) ◽  
pp. 89-96 ◽  
Author(s):  
Heidi Fiegl ◽  
Karim Elmasry
Keyword(s):  
Risk Assessment ◽  
Dna Methylation ◽  
Therapy Monitoring ◽  
Promoter Hypermethylation ◽  
Cancer Risk Assessment ◽  
Tumour Suppressor Genes ◽  
Molecular Alterations ◽  
Cancer Types ◽  
Cpg Dinucleotide ◽  
Aberrant Dna Methylation

Epigenetic alterations are heritable changes in gene expression without an accompanying change in primary DNA sequence. Two major mechanisms that cause epigenetic changes are post-translational histone modifications and DNA methylation at cytosine bases within a CpG dinucleotide. Epigenetic defects have turned out to be one of the most common molecular alterations in human neoplasia. Promoter hypermethylation is associated with loss of expression of tumour suppressor genes in cancer. The analysis of aberrant DNA methylation is gaining strength in the fields of cancer risk assessment, diagnosis, and therapy monitoring in different cancer types. These issues are discussed in this review.

Aberrant DNA Methylation Is Associated with Reduced Response to SRC Inhibition in Primary Human Vestibular Schwannoma Cells

2019 ◽  
Author(s):  
Christine Dinh ◽  
Juan Young ◽  
Olena Bracho ◽  
Rahul Mittal ◽  
Denise Yan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Vestibular Schwannoma ◽  
Aberrant Dna Methylation

245-LB: Aberrant DNA Methylation as a Contributor to Obesity-Associated Vascular Dysfunction

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 245-LB
Author(s):  
MOHAMED M. ALI ◽  
CHANDRA HASSAN ◽  
MARIO MASRUR ◽  
FRANCESCO BIANCO ◽  
SHANE A. PHILLIPS ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Vascular Dysfunction ◽  
Aberrant Dna Methylation

scholarly journals Neuroblastoma and the epigenome

2021 ◽  
Author(s):  
Irfete S. Fetahu ◽  
Sabine Taschner-Mandl
Keyword(s):  
Dna Methylation ◽  
Histone Modifications ◽  
Disease Diagnosis ◽  
Dna Methyltransferases ◽  
Epigenetic Alterations ◽  
Aberrant Expression ◽  
Tet Proteins ◽  
Relative Paucity ◽  
Underlying Causes ◽  
Aberrant Dna Methylation

AbstractNeuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system and one of the most common solid tumors in infancy. Amplification of MYCN, copy number alterations, numerical and segmental chromosomal aberrations, mutations, and rearrangements on a handful of genes, such as ALK, ATRX, TP53, RAS/MAPK pathway genes, and TERT, are attributed as underlying causes that give rise to NB. However, the heterogeneous nature of the disease—along with the relative paucity of recurrent somatic mutations—reinforces the need to understand the interplay of genetic factors and epigenetic alterations in the context of NB. Epigenetic mechanisms tightly control gene expression, embryogenesis, imprinting, chromosomal stability, and tumorigenesis, thereby playing a pivotal role in physio- and pathological settings. The main epigenetic alterations include aberrant DNA methylation, disrupted patterns of posttranslational histone modifications, alterations in chromatin composition and/or architecture, and aberrant expression of non-coding RNAs. DNA methylation and demethylation are mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, respectively, while histone modifications are coordinated by histone acetyltransferases and deacetylases (HATs, HDACs), and histone methyltransferases and demethylases (HMTs, HDMs). This article focuses predominately on the crosstalk between the epigenome and NB, and the implications it has on disease diagnosis and treatment.

scholarly journals Molecular diagnostics helps to identify distinct subgroups of spinal astrocytomas

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Annamaria Biczok ◽  
Felix L. Strübing ◽  
Julia M. Eder ◽  
Rupert Egensperger ◽  
Oliver Schnell ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Molecular Markers ◽  
Prognostic Significance ◽  
The Elderly ◽  
Molecular Profile ◽  
Diffuse Astrocytoma ◽  
Molecular Alterations ◽  
High Grade Astrocytoma ◽  
Dismal Prognosis ◽  
Few Data

AbstractPrimary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations in association with the clinical course. Histology and genome sequencing was performed in 26 spinal astrocytomas operated upon between 2000 and 2020. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations. Histology and NGS allowed the distinction of 5 tumor subgroups: glioblastoma IDH wildtype (GBM); diffuse midline glioma H3 K27M mutated (DMG-H3); high-grade astrocytoma with piloid features (HAP); diffuse astrocytoma IDH mutated (DA), diffuse leptomeningeal glioneural tumors (DGLN) and pilocytic astrocytoma (PA). Within all tumor entities GBM (median OS: 5.5 months), DMG-H3 (median OS: 13 months) and HAP (median OS: 8 months) showed a fatal prognosis. DMG-H3 tend to emerge in adolescence whereas GBM and HAP develop in the elderly. HAP are characterized by CDKN2A/B deletion and ATRX mutation. 50% of PA tumors carried a mutation in the PIK3CA gene which is seemingly associated with better outcome (median OS: PIK3CA mutated 107.5 vs 45.5 months in wildtype PA). This exploratory molecular profiling of spinal cord astrocytomas allows to identify distinct subgroups by combining molecular markers and histomorphology. DMG-H3 tend to develop in adolescence with a similar dismal prognosis like GBM and HAP in the elderly. We here describe spinal HAP with a distinct molecular profile for the first time.

scholarly journals Myocardial amyloidosis following multiple myeloma in a 38-year-old female patient: A case report

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 396-402
Author(s):  
Qisi Zhang ◽  
Yingli Qiao ◽  
Dongmei Yan ◽  
Yuhui Deng ◽  
Mengyang Zhang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Laboratory Data ◽  
Young Patients ◽  
Clinical Manifestations ◽  
The Elderly ◽  
First Episode ◽  
Rapid Progression ◽  
Congo Red Staining ◽  
Impaired Cardiac Function

AbstractMultiple myeloma (MM) is an immunoglobulin-producing tumor of plasma cells, which occurs commonly in the elderly. The incidence of myocardial amyloidosis with MM is extremely low and early clinical manifestations are nonspecific. The diversity of clinical manifestations and first episode symptoms often cause misdiagnosis in young patients with myocardial amyloidosis following MM. In this study, we analyzed the clinical data of a young woman with MM and impaired cardiac function combined with echocardiography, electrocardiography (ECG), laboratory data, cell Congo Red staining, and other manifestations to diagnose amyloidosis. Considering the rapid progression, short survival, and poor prognosis in most patients, a clear, definitive, and timely diagnosis is essential for the treatment of patients with MM complicated with myocardial amyloidosis.

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