scholarly journals Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma

2020 ◽  
Vol 9 (7) ◽  
pp. 705-714
Author(s):  
Anne Jouinot ◽  
Juliane Lippert ◽  
Martin Fassnacht ◽  
Bruno de La Villeon ◽  
Amandine Septier ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Markers ◽  
Adrenocortical Carcinoma ◽  
Somatic Mutations ◽  
Intratumor Heterogeneity ◽  
Tissue Samples ◽  
Molecular Alterations ◽  
Prognostic Assessment ◽  
Genomic Studies ◽  
Chromosome Alteration

Background: The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level. Methods: Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12). Results: Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients, respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were ‘Noisy’ (numerous and anarchic alterations) in 8/14 and ‘Chromosomal’ (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%). Conclusions: Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable and might be more robust for the prognostic assessment.

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: Adrenocortical carcinoma: differentiating the good from the poor prognosis tumors

2018 ◽  
Vol 178 (5) ◽  
pp. R215-R230 ◽  
Author(s):  
Anne Jouinot ◽  
Jérôme Bertherat
Keyword(s):  
Adrenocortical Carcinoma ◽  
Poor Prognosis ◽  
Tumor Biology ◽  
Tumor Grade ◽  
Proliferation Index ◽  
Adrenal Tumors ◽  
Molecular Alterations ◽  
Recurrent Mutations ◽  
Genomic Studies ◽  
Rare Malignancy

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis, the five-years overall survival being below 40%. However, there is great variability of outcomes and we have now a better view of the heterogeneity of tumor aggressiveness. The extent of the disease at the time of diagnosis, best assayed by the European Network for the Study of Adrenal Tumors (ENSAT) Staging Score, is a major determinant of survival. The tumor grade, including the mitotic count and the Ki67 proliferation index, also appears as a strong prognostic factor. The assessment of tumor grade, even by expert pathologists, still suffers from inter-observer reproducibility. The emergence of genomics in the last decade has revolutionized the knowledge of molecular biology and genetics of cancers. In ACC, genomic approaches – including pan-genomic studies of gene expression (transcriptome), recurrent mutations (exome or whole-genome sequencing), chromosome alterations, DNA methylation (methylome), miRNA expression (miRnome) – converge in a new classification of ACC, characterized by distinct molecular profiles and very different outcomes. Targeted measurements of a few discriminant molecular alterations have been developed in the perspective of clinical routine, and thus, may help defining therapeutic strategy. By individualizing patients’ prognosis and tumor biology, these recent progresses appear as an important step forward towards precision medicine.

scholarly journals A comparison of gene expression and DNA methylation patterns across tissues and species

2018 ◽  
Author(s):  
Lauren E. Blake ◽  
Julien Roux ◽  
Irene Hernando-Herraez ◽  
Nicholas E. Banovich ◽  
Raquel Garcia Perez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Rhesus Macaques ◽  
Sequence Divergence ◽  
Data Sets ◽  
Functional Genomic ◽  
Tissue Samples ◽  
Genomic Studies ◽  
Promoter Dna ◽  
Study Designs

AbstractPreviously published comparative functional genomic data sets from primates using frozen tissue samples, including many data sets from our own group, were collected and analyzed using non-optimal study designs and analysis approaches. In addition, when samples from multiple tissues were studied in a comparative framework, individual and tissue were confounded. We designed a multi-tissue comparative study of gene expression and DNA methylation in primates that minimizes confounding effects by using a balanced design with respect to species, tissues, and individuals. We also developed a comparative analysis pipeline that minimizes biases due to sequence divergence. We thus present the most comprehensive catalog of similarities and differences in gene expression and methylation levels between livers, kidneys, hearts, and lungs, in humans, chimpanzees, and rhesus macaques. We estimate that overall, only between 7 to 11% (depending on the tissue) of inter-species differences in gene expression levels can be accounted for by corresponding differences in promoter DNA methylation. However, gene expression divergence in conserved tissue-specific genes can be explained by corresponding inter-species methylation changes more often. We end the paper by providing recommendations for effective study design and best practices for meta-data recording for comparative functional genomic studies in primates.

scholarly journals Whole-exome sequencing identifies somatic mutations and intratumor heterogeneity in inflammatory breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Rui Luo ◽  
Weelic Chong ◽  
Qiang Wei ◽  
Zhenchao Zhang ◽  
Chun Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Inflammatory Breast Cancer ◽  
Somatic Mutations ◽  
Gene Mutations ◽  
Intratumor Heterogeneity ◽  
Driver Gene ◽  
Tissue Samples ◽  
Whole Exome

AbstractInflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Although it is a rare subtype, IBC is responsible for roughly 10% of breast cancer deaths. In order to obtain a better understanding of the genomic landscape and intratumor heterogeneity (ITH) in IBC, we conducted whole-exome sequencing of 16 tissue samples (12 tumor and four normal samples) from six hormone-receptor-positive IBC patients, analyzed somatic mutations and copy number aberrations, and inferred subclonal structures to demonstrate ITH. Our results showed that KMT2C was the most frequently mutated gene (42%, 5/12 samples), followed by HECTD1, LAMA3, FLG2, UGT2B4, STK33, BRCA2, ACP4, PIK3CA, and DNAH8 (all nine genes tied at 33% frequency, 4/12 samples). Our data indicated that PTEN and FBXW7 mutations may be considered driver gene mutations for IBC. We identified various subclonal structures and different levels of ITH between IBC patients, and mutations in the genes EIF4G3, IL12RB2, and PDE4B may potentially generate ITH in IBC.

scholarly journals Low Protein Expression of ATRX and ZNRF3 as a Novel Prognostic Marker of Adult Adrenocortical Carcinoma

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A87-A88
Author(s):  
Vânia Balderrama Brondani ◽  
Amanda Meneses Ferreira Lacombe ◽  
Beatriz Marinho Mariani ◽  
Luciana Ribeiro Montenegro ◽  
Ibere Soares Cauduro ◽  
...  
Keyword(s):  
Protein Expression ◽  
Adrenocortical Carcinoma ◽  
Tumor Size ◽  
Cox Model ◽  
Tumor Biology ◽  
Tissue Samples ◽  
Tertiary Referral Center ◽  
Low Protein ◽  
Dismal Prognosis ◽  
Genomic Studies

Abstract Adrenocortical carcinoma (ACC) is a rare malignant neoplasia that is usually associated with a dismal prognosis. ACC overall survival (OS) depends on the particular biology of the tumor. Pan-genomic studies have demonstrated the involvement of ATRX and ZNRF3 genes in adrenocortical tumorigenesis. Aim: To evaluate ATRX and ZNRF3 protein expression in a large cohort of adults with ACC followed at a single tertiary referral center to establish the prognostic value of these genes. Methods: Two pathologists analyzed immunohistochemically-stained slides for ATRX and ZNRF3 (blinded assessment) proteins using tissue microarrays comprising tissue samples from 82 ACC (kappa 0.854; P<0.001). Cohort: female 76.8%; median age 38.2 (15.3–85.4) years; 67.5% of patients presented with hypercortisolism; ENSAT stage 1, 11.12%; 2, 44.44%; 3 and 4: (44.44%). The median follow-up time was 39.58 (1.4–406.8) months; 39 patients died during this period. Low protein expression was defined as follows: ATRX, when < 25% of tumor cells were immunoreacted; ZNRF3, when a score < 3 (extension + intensity) was established. Results: Low ATRX protein expression was positively associated with the age at diagnosis (P< 0.001), and it was negatively correlated with tumor size (P=0.020) and with Weiss score (P=0.033). Low ZNRF3 protein expression correlated negatively with tumor weight (P=0.026), with tumor size (P= 0.005), and with Weiss score (P=0.002). Regarding OS, the low protein expression of ATRX and ZNRF3 was associated with a decrease of OS (P=0.045 and P=0.012, respectively). The Cox model for ATRX protein expression showed a HR of 0.521 (95% CI 0.273–0.997; P=0.049); for ZNRF3 expression, HR = 0.441 (95% CI 0.229–0.852; P=0.015). The combined protein expression of both genes was also associated with a decrease in OS in this cohort (P=0.02). The high ATRX and ZNRF3 protein expressions were positively associated with optimistic recurrence-free survival (P=0.027, P=0.005, respectively). Conclusion: The knowledge of tumor biology is an important step to deliver personalized medicine, affording the opportunity to design better clinical approaches and targeted therapies. This study brought pan-genomic studies closer to clinical practice with an easily accessible tool for stratifying patients with ACC. We demonstrated that low levels of protein expression of ATRX and ZNRF3 are negative prognostic markers of ACC.

GLIOBLASTOMA MULTIFORME: PATHOGENESIS AND MOLECULAR MARKERS

2017 ◽  
Vol 63 (5) ◽  
pp. 695-702
Author(s):  
Oleg Kit ◽  
Dmitriy Vodolazhskiy ◽  
Yelena Frantsiyants ◽  
Svetlana Panina ◽  
E. Rastorguev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumor ◽  
Molecular Markers ◽  
Glioblastoma Multiforme ◽  
Somatic Mutations ◽  
Web Of Science ◽  
Molecular Subtypes ◽  
Regulation Of Gene Expression ◽  
Signal Pathways ◽  
Poorly Differentiated

Glioblastoma multiforme (GBM) is the most common and invasive poorly differentiated brain tumor with nearly 100 % rate of recurrence and unfavorable prognosis. The aim of the present review is to analyze recent studies and experimental results (Scopus, Web of Science, PubMed) concerning somatic mutations in glioblastoma, aberrant regulation of gene expression of signal pathways including EGFR, TGFß, etc. and markers for GBM progression. Particularly the molecular subtypes of glioblastoma and NGS results are considered in this review.

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.

F65APPLICATION OF DNA METHYLATION MEASUREMENTS OF PERIPHERAL TISSUE SAMPLES IN CLINICAL EPIGENETICS

2019 ◽  
Vol 29 ◽  
pp. S1144-S1145
Author(s):  
Andrea Vereczkei ◽  
Szimonetta Turóczi ◽  
Emese Kruk ◽  
Kata Fazekas ◽  
Zsolt Unoka ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Peripheral Tissue ◽  
Tissue Samples

scholarly journals Age Prediction of Human Based on DNA Methylation by Blood Tissues

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 870
Author(s):  
Jiansheng Zhang ◽  
Hongli Fu ◽  
Yan Xu
Keyword(s):  
Dna Methylation ◽  
Pearson Correlation ◽  
Close Correlation ◽  
Gradient Boosting ◽  
Tissue Samples ◽  
Regression Methods ◽  
Cpg Sites ◽  
Testing Dataset ◽  
Age Related ◽  
Better Than

In recent years, scientists have found a close correlation between DNA methylation and aging in epigenetics. With the in-depth research in the field of DNA methylation, researchers have established a quantitative statistical relationship to predict the individual ages. This work used human blood tissue samples to study the association between age and DNA methylation. We built two predictors based on healthy and disease data, respectively. For the health data, we retrieved a total of 1191 samples from four previous reports. By calculating the Pearson correlation coefficient between age and DNA methylation values, 111 age-related CpG sites were selected. Gradient boosting regression was utilized to build the predictive model and obtained the R2 value of 0.86 and MAD of 3.90 years on testing dataset, which were better than other four regression methods as well as Horvath’s results. For the disease data, 354 rheumatoid arthritis samples were retrieved from a previous study. Then, 45 CpG sites were selected to build the predictor and the corresponded MAD and R2 were 3.11 years and 0.89 on the testing dataset respectively, which showed the robustness of our predictor. Our results were better than the ones from other four regression methods. Finally, we also analyzed the twenty-four common CpG sites in both healthy and disease datasets which illustrated the functional relevance of the selected CpG sites.

scholarly journals CpGmotifs: a tool to discover DNA motifs associated to CpG methylation events

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Giovanni Scala ◽  
Antonio Federico ◽  
Dario Greco
Keyword(s):  
Dna Methylation ◽  
Motif Discovery ◽  
Cpg Methylation ◽  
Functional Interpretation ◽  
Dna Motifs ◽  
Molecular Alterations ◽  
Link Type ◽  
Dna Motif ◽  
Quantitative Manner ◽  
Dna Motif Discovery

Abstract Background The investigation of molecular alterations associated with the conservation and variation of DNA methylation in eukaryotes is gaining interest in the biomedical research community. Among the different determinants of methylation stability, the DNA composition of the CpG surrounding regions has been shown to have a crucial role in the maintenance and establishment of methylation statuses. This aspect has been previously characterized in a quantitative manner by inspecting the nucleotidic composition in the region. Research in this field still lacks a qualitative perspective, linked to the identification of certain sequences (or DNA motifs) related to particular DNA methylation phenomena. Results Here we present a novel computational strategy based on short DNA motif discovery in order to characterize sequence patterns related to aberrant CpG methylation events. We provide our framework as a user-friendly, shiny-based application, CpGmotifs, to easily retrieve and characterize DNA patterns related to CpG methylation in the human genome. Our tool supports the functional interpretation of deregulated methylation events by predicting transcription factors binding sites (TFBS) encompassing the identified motifs. Conclusions CpGmotifs is an open source software. Its source code is available on GitHub https://github.com/Greco-Lab/CpGmotifs and a ready-to-use docker image is provided on DockerHub at https://hub.docker.com/r/grecolab/cpgmotifs.

Molecular Diagnostics of Thyroid Tumors

2011 ◽  
Vol 135 (5) ◽  
pp. 569-577 ◽  
Author(s):  
Yuri E. Nikiforov
Keyword(s):  
Thyroid Cancer ◽  
Molecular Markers ◽  
Fine Needle Aspiration ◽  
Thyroid Nodules ◽  
Needle Aspiration ◽  
Genetic Alterations ◽  
Braf V600e ◽  
Fine Needle ◽  
Molecular Alterations ◽  
Diagnostic Use

Abstract Context.—Thyroid cancer is the most common type of endocrine malignancy and its incidence is steadily increasing. Papillary carcinoma and follicular carcinoma are the most common types of thyroid cancer and represent those tumor types for which use of molecular markers for diagnosis and prognostication is of high clinical significance. Objective.—To review the most common molecular alterations in thyroid cancer and their diagnostic and prognostic utility. Data Sources.—PubMed (US National Library of Medicine)–available review articles, peer-reviewed original articles, and experience of the author. Conclusions.—The most common molecular alterations in thyroid cancer include BRAF and RAS point mutations and RET/PTC and PAX8/PPARγ rearrangements. These nonoverlapping genetic alterations are found in more than 70% of papillary and follicular thyroid carcinomas. These molecular alterations can be detected in surgically resected samples and fine-needle aspiration samples from thyroid nodules and can be of significant diagnostic use. The diagnostic role of BRAF mutations has been studied most extensively, and recent studies also demonstrated a significant diagnostic utility of RAS, RET/PTC, and PAX8/PPARγ mutations, particularly in thyroid fine-needle aspiration samples with indeterminate cytology. In addition to the diagnostic use, BRAF V600E mutation can also be used for tumor prognostication, as this mutation is associated with higher rate of tumor recurrence and tumor-related mortality. The use of these and other emerging molecular markers is expected to improve significantly the accuracy of cancer diagnosis in thyroid nodules and allow more individualized surgical and postsurgical management of patients with thyroid cancer.

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