scholarly journals ENDOCRINE TUMOURS: Advances in the molecular pathogenesis of thyroid cancer: lessons from the cancer genome

2016 ◽  
Vol 175 (5) ◽  
pp. R203-R217 ◽  
Author(s):  
Garcilaso Riesco-Eizaguirre ◽  
Pilar Santisteban
Keyword(s):  
Thyroid Cancer ◽  
Cancer Genomics ◽  
Treatment Strategies ◽  
Genetic Alterations ◽  
Cancer Genome ◽  
Molecular Pathogenesis ◽  
Cancer Genes ◽  
New Information ◽  
Novel Treatment Strategies ◽  
And Behavior

Thyroid cancer is the most common endocrine malignancy giving rise to one of the most indolent solid cancers, but also one of the most lethal. In recent years, systematic studies of the cancer genome, most importantly those derived from The Cancer Genome Altas (TCGA), have catalogued aberrations in the DNA, chromatin, and RNA of the genomes of thousands of tumors relative to matched normal cellular genomes and have analyzed their epigenetic and protein consequences. Cancer genomics is therefore providing new information on cancer development and behavior, as well as new insights into genetic alterations and molecular pathways. From this genomic perspective, we will review the main advances concerning some essential aspects of the molecular pathogenesis of thyroid cancer such as mutational mechanisms, new cancer genes implicated in tumor initiation and progression, the role of non-coding RNA, and the advent of new susceptibility genes in thyroid cancer predisposition. This look across these genomic and cellular alterations results in the reshaping of the multistep development of thyroid tumors and offers new tools and opportunities for further research and clinical development of novel treatment strategies.

scholarly journals DNA methylation in thyroid cancer

2019 ◽  
Vol 26 (7) ◽  
pp. R415-R439 ◽  
Author(s):  
Carles Zafon ◽  
Joan Gil ◽  
Beatriz Pérez-González ◽  
Mireia Jordà
Keyword(s):  
Dna Methylation ◽  
Thyroid Cancer ◽  
Cancer Genomics ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
Epigenetic Mechanism ◽  
Aberrant Methylation ◽  
Technological Advances ◽  
Molecular Landscape

In recent years, cancer genomics has provided new insights into genetic alterations and signaling pathways involved in thyroid cancer. However, the picture of the molecular landscape is not yet complete. DNA methylation, the most widely studied epigenetic mechanism, is altered in thyroid cancer. Recent technological advances have allowed the identification of novel differentially methylated regions, methylation signatures and potential biomarkers. However, despite recent progress in cataloging methylation alterations in thyroid cancer, many questions remain unanswered. The aim of this review is to comprehensively examine the current knowledge on DNA methylation in thyroid cancer and discuss its potential clinical applications. After providing a general overview of DNA methylation and its dysregulation in cancer, we carefully describe the aberrant methylation changes in thyroid cancer and relate them to methylation patterns, global hypomethylation and gene-specific alterations. We hope this review helps to accelerate the use of the diagnostic, prognostic and therapeutic potential of DNA methylation for the benefit of thyroid cancer patients.

A heuristic platform for clinical interpretation of cancer genome sequencing data.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10502-10502
Author(s):  
Eliezer Mendel Van Allen ◽  
Nikhil Wagle ◽  
Gregory Kryukov ◽  
Alexis Ramos ◽  
Gad Getz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genome Sequencing ◽  
Heuristic Algorithm ◽  
Genetic Alterations ◽  
Cancer Genome ◽  
Clinical Samples ◽  
Whole Genome ◽  
Cancer Genes ◽  
Sequencing Data ◽  
Clinical Interpretation

10502 Background: The ability to identify and effectively sort the full spectrum of biologically and therapeutically relevant genetic alterations identified by massively parallel sequencing may improve cancer care. A major challenge involves rapid and rational categorization of data-intensive output, including somatic mutations, insertions/deletions, copy number alterations, and rearrangements into ranked categories for clinician review. Methods: A database of clinically actionable alterations was created, consisting of over 100 annotated genes known to undergo somatic genomic alterations in cancer that may impact clinical decision-making. A heuristic algorithm was developed, which selectively identifies somatic alterations based on the clinically actionable alterations database. Remaining variants are sorted based on additional heuristics, including high priority alterations based on presence in the Cancer Gene Census, biologically significant cancer genes based on presence in COSMIC or MSigDB, and low priority alterations in the same gene family as biologically significant cancer genes. The heuristic algorithm was applied to whole exome sequencing data of clinical samples and whole genome sequencing data from a cohort of prostate cancer samples processed using established Broad Institute pipelines. Results: Application of the heuristic algorithm to the prostate cancer whole genome rearrangement data identified 172 (out of 5978) rearrangements involving actionable genes (averaging 2-3 events per tumor). Furthermore, two clinical samples processed prospectively were analyzed, yielding three potentially actionable alterations for clinical review. Conclusions: The heuristic model for clinical interpretation of next generation sequencing data may facilitate rapid analysis of tumor genomic information for clinician review by identifying and prioritizing alterations that can directly impact care. Our platform can also be applied to research data to prospectively explore clinically relevant findings from existing cohorts. Future analytical approaches using heuristic or probabilistic algorithms should underpin a robust prospective assessment of clinical cancer genome data.

scholarly journals The Molecular Pathogenesis of Trichilemmal Carcinoma

2020 ◽  
Author(s):  
Jeong Hyun Ha ◽  
Cheol Lee ◽  
Kyu Sang Lee ◽  
Chang-sik Pak ◽  
Choong-Hyun Sun ◽  
...  
Keyword(s):  
Clinical Course ◽  
Genetic Alterations ◽  
Molecular Pathogenesis ◽  
Cancer Genes ◽  
Genetic Changes ◽  
Tp53 Mutations ◽  
Truncating Mutation ◽  
Skin Cancers ◽  
Aggressive Clinical Course ◽  
Insight Into

Abstract Background : Trichilemmal carcinoma (TC) is an extremely rare hair follicle tumor. We aimed to explore the genetic abnormalities involved in TC to gain insight into its molecular pathogenesis. Methods : Data from patients diagnosed with TC within a 12-year period were retrospectively reviewed. Genomic DNA isolated from a formalin-fixed paraffin-embedded (FFPE) tumor tissue block was sequenced and explored for a panel of cancer genes. Results : DNA was extracted from the FFPE tissue of four patients (50% female; mean age, 51.5 years) diagnosed with TC for analysis. The tumor was located in the head and neck of three patients and in the shoulder of one patient. TP53 mutations (p.Arg213*, p.Arg249Trp, and p.Arg248Gln) were found in three patients. Fusions previously identified in melanoma were detected in two patients ( TACC3-FGFR3 and ROS1-GOPC fusions). Other mutations found included NF1-truncating mutation (Arg1362*), NRAS mutation (p.Gln61Lys), TOP1 amplification, and PTEN deletion. Overall, genetic changes found in TC resemble that of other skin cancers, suggesting similar pathogenesis. All patients with TP53 mutations had aggressive clinical course, two who died (OS 93 and 36 months), and one who experienced recurrent relapse. Conclusions : We reported the genomic variations found in TC, which may give insight into the molecular pathogenesis. Overall, genetic changes found in TC resembled that of other skin cancers, suggesting similar pathogenesis. TP53 mutations was were identified in patients who had an aggressive clinical course. Genetic alterations identified may further suggest the potential treatment options of TC.

Genetic analysis of colorectal cancers in young patients.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 632-632
Author(s):  
Andrea M. Abbott ◽  
Nishi Kothari ◽  
Jamie K. Teer ◽  
Thejal Srikumar ◽  
Richard D. Kim ◽  
...  
Keyword(s):  
Large Scale ◽  
Scale Validation ◽  
Young Patients ◽  
Treatment Strategies ◽  
Genetic Alterations ◽  
Cancer Genes ◽  
Old Patients ◽  
Younger Patients ◽  
Exact Test ◽  
Worse Prognosis

632 Background: The incidence of colorectal cancer (CRC) is increasing in adults <50 years old and these cases may be associated with a worse prognosis. Despite our growing understanding of genetic conditions, a substantial number of CRC in young patients are classified as sporadic but may harbor unique molecular changes. We sought to compare profiles of genetic alterations between young and old patients who lack defects in known hereditary cancer genes. Methods: 283 CRC cases diagnosed between 1998 and 2010 were analyzed by targeted exome sequencing using the Illumina NGS platform with 50-100x coverage. Filtering of normal variants was performed using 1000 Genomes to enrich for somatic mutations which were then limited to those predicted to alter protein sequence. The younger and older cohorts were defined as ≤45 and ≥65 years old at diagnosis, respectively. Patients found to be MSI-high (n= 2 young, 50 old) or with a known hereditary syndrome (n=6) were excluded. For this preliminary screen, Fisher’s Exact test was used to detect differences in mutation frequencies. Results: A total of 195 older and 30 younger patients with median ages of 73 (range 65-93) and 42 (range 30-45) years respectively, were analyzed. We identified 57 genes with significant differential mutation frequencies. The top ten genes mutated with increased in frequency in the younger cohort are shown in Table 1. Conclusions: In this exploratory project, we identified mutations that occurred more frequently in younger CRC patients. Large scale validation of these findings and application of this approach may lead to novel screening and treatment strategies in younger patients [Table: see text]

scholarly journals NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021

2021 ◽  
Vol 19 (1) ◽  
pp. 16-27
Author(s):  
Daniel A. Pollyea ◽  
Dale Bixby ◽  
Alexander Perl ◽  
Vijaya Raj Bhatt ◽  
Jessica K. Altman ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Decision Making ◽  
Treatment Strategies ◽  
Clinical Decision ◽  
Genetic Alterations ◽  
Nccn Guidelines ◽  
New Information ◽  
Prognostic Importance ◽  
Acute Myeloid

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

Bladder cancer genomics

2020 ◽  
Vol 87 (2) ◽  
pp. 49-56
Author(s):  
Salvatore Siracusano ◽  
Riccardo Rizzetto ◽  
Antonio Benito Porcaro
Keyword(s):  
Bladder Cancer ◽  
Cancer Genomics ◽  
Treatment Strategies ◽  
Genetic Alterations ◽  
Point Of View ◽  
The Cancer Genome Atlas ◽  
Molecular Alterations ◽  
Cancer Genome Atlas ◽  
Polymerase Chain ◽  
Muscle Invasive

Until recently, the treatment of bladder cancer, for several years, was limited to surgery and to immunotherapy or chemotherapy. Currently, the extensive analysis of molecular alterations has led to novel treatment approaches. The advent of polymerase chain reaction and genomic hybridization techniques has allowed to investigate alterations involved in bladder cancer at DNA level. By this way, bladder cancers can be classified as papillary or non-papillary based on genetic alterations with activation or mutations in FGFR3 papillary tumors and with inactivation or mutations involving TP53 and RB1 in non-papillary tumors. Recently, the patterns of gene expression allow to differentiate basal and luminal subtypes as reported in breast cancer. In particular, basal cancers are composed of squamous and sarcomatoid pathological findings, while luminal cancers are composed of papillary finding features and genetic mutations (FGFR3). In particular, specific investigative studies demonstrated that luminal cancers are associated with secondary muscle invasive cancer while basal tumors are related to advanced disease since they are often metastatic at diagnosis. Moreover, from therapeutic point of view, different researchers showed that mutations of DNA are related to the sensitivity of bladder cancer while performing cisplatin chemotherapy. In this prospective, the bladder cancer molecular subtyping classification might allow identifying the set of patients who can safely avoid neoadjuvant chemotherapy likely because of the low response to systemic chemotherapy (chemoresistant tumors). In this context, the Cancer Genome Atlas (TCGA) project has improved the knowledge of the molecular targets of invasive urothelial cancers allowing the researchers to propose hypothesis suggesting that agents targeting the genomic alterations may be an effective strategy in managing these cancers, which occur in about 68% of muscle invasive cancers. A future goal will be to combine treatment strategies of invasive bladder cancers according to their genetic mutational load defined by molecular pathology.

scholarly journals Genomic landscape of pancreatic neuroendocrine tumours: the International Cancer Genome Consortium

2018 ◽  
Vol 236 (3) ◽  
pp. R161-R167 ◽  
Author(s):  
Andrea Mafficini ◽  
Aldo Scarpa
Keyword(s):  
Neuroendocrine Tumours ◽  
Genetic Alterations ◽  
Cancer Genome ◽  
The Body ◽  
Genetic Syndromes ◽  
International Cancer Genome Consortium ◽  
Molecular Alterations ◽  
New Information ◽  
Pancreatic Neuroendocrine Tumours ◽  
Genome Consortium

Neuroendocrine tumours (NETs) may arise throughout the body and are a highly heterogeneous, relatively rare class of neoplasms difficult to study also for the lack of disease models. Despite this, knowledge on their molecular alterations has expanded in the latest years, also building from genetic syndromes causing their onset. Pancreatic NETs (PanNETs) have been among the most studied, and research so far has outlined a series of recurring features, as inactivation of MEN1, VHL, TSC1/2 genes and hyperactivation of the PI3K/mTOR pathway. Next-generation sequencing has added new information by showing the key role of alternative lengthening of telomeres, driven in a fraction of PanNETs by inactivation of ATRX/DAXX. Despite this accumulation of knowledge, single studies often relied on few cases or were limited to the DNA, RNA, protein or epigenetic level with lack of integrative analysis. The International Cancer Genome Consortium aimed at removing these barriers through a strict process of data and samples collection, to produce whole-genome integrated analyses for many tumour types. The results of this effort on PanNETs have been recently published and, while confirming previous observations provide a first snapshot of how heterogeneous is the combination of genetic alterations that drive this tumour type, yet converging into four pathways whose alteration has been enriched by newly discovered mechanisms. While calling for further integration of genetic and epigenetic analyses, these data allow to reconcile previous findings in a defined frame and may provide clinical research with markers for patients stratification and to guide targeted therapy decisions.

scholarly journals The Molecular Pathogenesis of Trichilemmal Carcinoma

2020 ◽  
Author(s):  
Jeong Hyun Ha ◽  
Cheol Lee ◽  
Kyu Sang Lee ◽  
Chang-sik Pak ◽  
Choong-Hyun Sun ◽  
...  
Keyword(s):  
Clinical Course ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Molecular Pathogenesis ◽  
Cancer Genes ◽  
Genetic Changes ◽  
Truncating Mutation ◽  
Skin Cancers ◽  
Aggressive Clinical Course ◽  
Insight Into

Abstract Background: Trichilemmal carcinoma (TC) is an extremely rare hair follicle tumor. We aimed to explore the genetic abnormalities involved in TC to gain insight into its molecular pathogenesis.Methods: Data from patients diagnosed with TC within a 12-year period were retrospectively reviewed. Genomic DNA isolated from a formalin-fixed paraffin-embedded (FFPE) tumor tissue block was sequenced and explored for a panel of cancer genes.Results: DNA was extracted from the FFPE tissue of four patients (50% female; mean age, 51.5 years) diagnosed with TC for analysis. The tumor was located in the head and neck of three patients and in the shoulder of one patient. TP53 mutations (p.Arg213*, p.Arg249Trp, and p.Arg248Gln) were found in three patients. Fusions previously identified in melanoma were detected in two patients (TACC3-FGFR3 and ROS1-GOPC fusions). Other mutations found included NF1-truncating mutation (Arg1362*), NRAS mutation (p.Gln61Lys), TOP1 amplification, and PTEN deletion. Overall, genetic changes found in TC resemble that of other skin cancers, suggesting similar pathogenesis. All patients with TP53 mutations had aggressive clinical course, two who died (OS 93 and 36 months), and one who experienced recurrent relapse.Conclusions: We reported the genomic variations found in TC, which may give insight into the molecular pathogenesis. Overall, genetic changes found in TC resembled that of other skin cancers, suggesting similar pathogenesis. TP53 mutations was were identified in patients who had an aggressive clinical course. Genetic alterations identified may further suggest the potential treatment options of TC.

scholarly journals Recurrent alternative splicing isoform switches in tumor samples provide novel signatures of cancer

2014 ◽  
Author(s):  
Endre Sebestyén ◽  
Michał Zawisza ◽  
Eduardo Eyras
Keyword(s):  
Alternative Splicing ◽  
Somatic Mutations ◽  
Cancer Genomics ◽  
Genetic Alterations ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Sequencing Data ◽  
Low Frequencies ◽  
Cancer Subtypes ◽  
Alternatively Spliced

Cancer genomics has been instrumental to determine the genetic alterations that are predictive of various tumor conditions. However, the majority of these alterations occur at low frequencies, motivating the need to expand the catalogue of cancer signatures. Alternative pre-mRNA splicing alterations, which bear major importance for the understanding of cancer, have not been exhaustively studied yet in the context of recent cancer genome projects. In this article we analyze RNA sequencing data for more than 4000 samples from The Cancer Genome Atlas (TCGA) project, including paired normal samples, to detect recurrent alternative splicing isoform switches in 9 different cancer types. We first investigate whether alternative splicing isoform changes are predictive of tumors by applying a rank-based algorithm based on the reversal of the relative expression of transcript isoforms. We find that consistent alternative splicing isoform changes can separate with high accuracy tumor and normal samples, as well as some cancer subtypes. We then searched for those changes that occur in the most abundant isoform, i.e isoform switches, and are therefore more likely to have a functional impact. In total we detected 244 isoform switches, which are associated to functional pathways that are frequently altered in cancer and also separate tumor and normal samples accurately. We further assessed whether these isoform changes are associated to somatic mutations. Surprisingly, only a few cases appear to have association, including the putative tumor suppressor FBLN2 and the tumor driver MYH11, which show association of an isoform switch to mutations and indels on the alternatively spliced exon. However, the number of observed mutations is in general not sufficient to explain the frequency of the found isoform switches, suggesting that recurrent isoform switching in cancer is mostly independent of somatic mutations. In summary, we present an effective approach to detect novel alternative splicing signatures that are predictive of tumors. Moreover, the same methodology has led to uncover recurrent isoform switches in tumors, which may provide novel prognostic and therapeutic targets. Software and data are available at: https://bitbucket.org/regulatorygenomicsupf/iso-ktsp and http://dx.doi.org/10.6084/m9.figshare.1061917

Advances in molecular pathogenesis thyroid cancer: therapeutic implications

2014 ◽  
Author(s):  
Pilar Santisteban ◽  
Ana Sastre-Perona ◽  
Leon Wert-Lamas ◽  
Garcilaso Riesco-Eizaguirre
Keyword(s):  
Thyroid Cancer ◽  
Molecular Pathogenesis ◽  
Therapeutic Implications
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