scholarly journals Μελέτη μοριακών σηματοδοτικών μηχανισμών επαγωγής της κυτταρικής επιβίωσης και αποδιαφοροποίησης στον καρκίνο

2019 ◽  
Author(s):  
Ευστάθιος-Ιάσων Βλαχάβας
Keyword(s):  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Rna Seq ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Ο όρος καρκίνος χρησιμοποιείται όχι για μια ασθένεια, αλλά για ένα ευρύτερο σύνολο συσχετιζόμενων νοσημάτων, οι οποίες περιγράφονται από ένα κοινό χαρακτηριστικό: την αφύσικη ανάπτυξη κυττάρων που διαιρούνται ανεξέλεγκτα και μπορούν να διηθήσουν παρακείμενους ιστούς. Η μελέτη των μοριακών μηχανισμών που εμπλέκονται στη παθοφυσιολογία των καρκίνου, αποτελεί πεδίο έντονης έρευνας, γιατί η κατανόησή τους συνδέεται άμεσα με την ορθή αντιμετώπιση της νόσου. Στην παρούσα διατριβή, εστιάζουμε στον καρκίνο του παχέος εντέρου. Η πλειοψηφία των όγκων του παχέος εντέρου είναι αδενοκαρκινώματα, τα οποία προκύπτουν από τη δημιουργία πολυπόδων που σχηματίζονται στο εσωτερικό τοίχωμα του παχέος εντέρου και μπορούν να εξελιχθούν σε νεοπλασίες. Ο καρκίνος του παχέος εντέρου είναι μια ιδιαίτερα σύνθετη ασθένεια, με έντονα μεταβλητά μοριακά και γενετικά χαρακτηριστικά και με διαφορική απόκριση σε φαρμακευτικά σχήματα. Περίπου το 40% των περιπτώσεων ανιχνεύονται σε πρώιμο στάδιο με το ποσοστό της πενταετούς επιβίωσης να κυμαίνεται στο 90%. Επιπρόσθετα, αποτελεί μια αιτία θνησιμότητας στις χώρες του ανεπτυγμένου κόσμου, κυρίως λόγω του υψηλού μεταστατικού δυναμικού που παρουσιάζει. Συνολικά, τα παραπάνω στοιχεία καθιστούν επιτακτική την αξιοποίηση όλων των διαθέσιμων μοριακών πληροφοριών αλλά και ιατροβιολογικών δεδομένων για την εφαρμογή εξατομικευμένης θεραπείας στα πλαίσια της μεταφραστικής έρευνας.Την τελευταία δεκαετία, η εκτεταμένη αξιοποίηση των τεχνικών υψηλής απόδοσης, όπως οι μικροσυστοιχίες γονιδίων και οι τεχνολογίες αλληλούχισης νέας γενιάς για την ανάλυση της γονιδιακής έκφρασης σε διάφορους τύπους καρκίνου του παχέος εντέρου, συνέβαλε σημαντικά στην ταυτοποίηση σημαντικών γονιδιακών μεταλλαγών και στον χαρακτηρισμό γονιδίων που εμπλέκονται στην παθοφυσιολογία του συγκεκριμένου καρκίνου. Αν και οι τεχνολογίες αλληλούχισης νέας γενιάς παρουσιάζουν σημαντικές τεχνολογικές βελτιώσεις, οι μικροσυστοιχίες DNA εξακολουθούν να παραμένουν δημοφιλείς για την ανάλυση του μεταγραφώματος, αφενός γιατί παραμένουν πιο οικονομικές και αφετέρου προϋποθέτουν μια λιγότερο σύνθετη προετοιμασία δειγμάτων, συγκριτικά με τις μεθοδολογίες αλληλούχισης. Αντιπροσωπευτικά παραδείγματα για τη συμβολή των τεχνολογιών υψηλής απόδοσης αποτελούν ερευνητικές δημοσιεύσεις από τη διεθνή ερευνητική συνεργασία (The Cancer Genome Atlas) για τον μοριακό χαρακτηρισμού του καρκίνου του παχέος εντέρου, καθώς και τον χαρακτηρισμό συγκεκριμένων μοριακών υποτύπων με βάση γονιδιωματικά δεδομένα από διαφορετικές ερευνητικές ομάδες. Ωστόσο, η ιδιαίτερη ετερογένεια που παρουσιάζει ο συγκεκριμένος καρκίνος αλλά και η δυσκολία της ερμηνείας μοριακών δεδομένων υψηλής διαστασιμότητας που προκύπτουν από την ανάλυση μικροσυστοιχιών αλλά και DNA/RNA-Seq τεχνολογιών, δυσχεραίνουν την αξιοποίηση των διαφόρων γονιδιακών υπογραφών που περιγράφουν ένα συγκεκριμένο καρκινικό φαινότυπο, στην κλινική εφαρμογή.

scholarly journals PR/SET Domain Family and Cancer: Novel Insights from the Cancer Genome Atlas

2018 ◽  
Vol 19 (10) ◽  
pp. 3250 ◽  
Author(s):  
Anna Sorrentino ◽  
Antonio Federico ◽  
Monica Rienzo ◽  
Patrizia Gazzerro ◽  
Maurizio Bifulco ◽  
...  
Keyword(s):  
Family Members ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Driver Gene ◽  
Rna Seq ◽  
Set Domain ◽  
Primary Tumors ◽  
Cancer Genome Atlas ◽  
Pan Cancer ◽  
Genome Atlas

The PR/SET domain gene family (PRDM) encodes 19 different transcription factors that share a subtype of the SET domain [Su(var)3-9, enhancer-of-zeste and trithorax] known as the PRDF1-RIZ (PR) homology domain. This domain, with its potential methyltransferase activity, is followed by a variable number of zinc-finger motifs, which likely mediate protein–protein, protein–RNA, or protein–DNA interactions. Intriguingly, almost all PRDM family members express different isoforms, which likely play opposite roles in oncogenesis. Remarkably, several studies have described alterations in most of the family members in malignancies. Here, to obtain a pan-cancer overview of the genomic and transcriptomic alterations of PRDM genes, we reanalyzed the Exome- and RNA-Seq public datasets available at The Cancer Genome Atlas portal. Overall, PRDM2, PRDM3/MECOM, PRDM9, PRDM16 and ZFPM2/FOG2 were the most mutated genes with pan-cancer frequencies of protein-affecting mutations higher than 1%. Moreover, we observed heterogeneity in the mutation frequencies of these genes across tumors, with cancer types also reaching a value of about 20% of mutated samples for a specific PRDM gene. Of note, ZFPM1/FOG1 mutations occurred in 50% of adrenocortical carcinoma patients and were localized in a hotspot region. These findings, together with OncodriveCLUST results, suggest it could be putatively considered a cancer driver gene in this malignancy. Finally, transcriptome analysis from RNA-Seq data of paired samples revealed that transcription of PRDMs was significantly altered in several tumors. Specifically, PRDM12 and PRDM13 were largely overexpressed in many cancers whereas PRDM16 and ZFPM2/FOG2 were often downregulated. Some of these findings were also confirmed by real-time-PCR on primary tumors.

scholarly journals Potential prognostic impact of EBV RNA‐seq reads in gastric cancer: a reanalysis of The Cancer Genome Atlas cohort

FEBS Open Bio ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 455-467 ◽  
Author(s):  
Daichi Sadato ◽  
Mina Ogawa ◽  
Chizuko Hirama ◽  
Tsunekazu Hishima ◽  
Shin‐Ichiro Horiguchi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Prognostic Impact ◽  
Rna Seq ◽  
Cancer Genome Atlas ◽  
Genome Atlas

scholarly journals Possible Human Papillomavirus 38 Contamination of Endometrial Cancer RNA Sequencing Samples in The Cancer Genome Atlas Database

2015 ◽  
Vol 89 (17) ◽  
pp. 8967-8973 ◽  
Author(s):  
Majid Kazemian ◽  
Min Ren ◽  
Jian-Xin Lin ◽  
Wei Liao ◽  
Rosanne Spolski ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Human Papillomavirus ◽  
Rna Sequencing ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Clinical Samples ◽  
Cross Contamination ◽  
Rna Seq ◽  
Cancer Genome Atlas ◽  
Genome Atlas

ABSTRACTViruses are causally associated with a number of human malignancies. In this study, we sought to identify new virus-cancer associations by searching RNA sequencing data sets from >2,000 patients, encompassing 21 cancers from The Cancer Genome Atlas (TCGA), for the presence of viral sequences. In agreement with previous studies, we found human papillomavirus 16 (HPV16) and HPV18 in oropharyngeal cancer and hepatitis B and C viruses in liver cancer. Unexpectedly, however, we found HPV38, a cutaneous form of HPV associated with skin cancer, in 32 of 168 samples from endometrial cancer. In 12 of the HPV38-positive (HPV38+) samples, we observed at least one paired read that mapped to both human and HPV38 genomes, indicative of viral integration into the host DNA, something not previously demonstrated for HPV38. The expression levels of HPV38 transcripts were relatively low, and all 32 HPV38+samples belonged to the same experimental batch of 40 samples, whereas none of the other 128 endometrial carcinoma samples were HPV38+, raising doubts about the significance of the HPV38 association. Moreover, the HPV38+samples contained the same 10 novel single nucleotide variations (SNVs), leading us to hypothesize that one patient was infected with this new isolate of HPV38, which was integrated into his/her genome and may have cross-contaminated other TCGA samples within batch 228. Based on our analysis, we propose guidelines to examine the batch effect, virus expression level, and SNVs as part of next-generation sequencing (NGS) data analysis for evaluating the significance of viral/pathogen sequences in clinical samples.IMPORTANCEHigh-throughput RNA sequencing (RNA-Seq), followed by computational analysis, has vastly accelerated the identification of viral and other pathogenic sequences in clinical samples, but cross-contamination during the processing of the samples remain a major problem that can lead to erroneous conclusions. We found HPV38 sequences specifically present in RNA-Seq samples from endometrial cancer patients from TCGA, a virus not previously associated with this type of cancer. However, multiple lines of evidence suggest possible cross-contamination in these samples, which were processed together in the same batch. Despite this potential cross-contamination, our data indicate that we have detected a new isolate of HPV38 that appears to be integrated into the human genome. We also provide general guidelines for computational detection and interpretation of pathogen-disease associations.

scholarly journals Identification of molecular targets for esophageal carcinoma diagnosis using miRNA-seq and RNA-seq data from The Cancer Genome Atlas: a study of 187 cases

Oncotarget ◽  
2017 ◽  
Vol 8 (22) ◽  
pp. 35681-35699 ◽  
Author(s):  
Jiang-Hui Zeng ◽  
Dan-Dan Xiong ◽  
Yu-Yan Pang ◽  
Yu Zhang ◽  
Rui-Xue Tang ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Molecular Targets ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Rna Seq ◽  
Cancer Genome Atlas ◽  
Genome Atlas

scholarly journals Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel–Hypermutated Cancer Genome and Comutation of POLD1 and MLH1

2017 ◽  
pp. 1-12
Author(s):  
Manish R. Sharma ◽  
James T. Auman ◽  
Nirali M. Patel ◽  
Juneko E. Grilley-Olson ◽  
Xiaobei Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Somatic Mutation ◽  
Mutation Rate ◽  
Germ Line ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Response To Chemotherapy ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A [p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel–hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.

scholarly journals The construction and analysis of ceRNA networks in invasive breast cancer: a study based on The Cancer Genome Atlas

2018 ◽  
Vol Volume 11 ◽  
pp. 1-11 ◽  
Author(s):  
Chundi Gao ◽  
Huayao Li ◽  
Jing Zhuang ◽  
HongXiu Zhang ◽  
Kejia Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Invasive Breast Cancer ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Genome Atlas
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