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Road-mapping the serrated pathway of colon tumorigenesis: Step 1: Epigenetic profiling of precancerous, proximal-colon lesions in women.

English title Road-mapping the serrated pathway of colon tumorigenesis: Step 1: Epigenetic profiling of precancerous, proximal-colon lesions in women.
Applicant Marra Giancarlo
Number 160163
Funding scheme Project funding (Div. I-III)
Research institution Institut für Molekulare Krebsforschung Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Molecular Biology
Start/End 01.05.2015 - 30.04.2018
Approved amount 429'000.00
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All Disciplines (2)

Discipline
Molecular Biology
Clinical Cancer Research

Keywords (5)

gene expression; large intestine; sessile serrated adenoma/polyp; epigenomics; molecular diagnosis

Lay Summary (German)

Lead
Der beschränkte Erfolg, welcher in der Prävention proximaler Kolorektalkarzinome zu verzeichnen ist, wird teilweise der in dieser Region des Darmtraktes höheren Prävalenz von flachen präkanzerösen Läsionen zugeschrieben. Diese entwickeln sich seitlich; klassische Kolonpolypen protrudieren ins Darmlumen. Die flachen präkanzerösen Läsionen sind nicht nur schwerer identifizier- und exzidierbar, sie werden öfter auch missdiagnostiziert als nicht-maligne Läsionen. Diese Missdiagnose ist folgenreich, insbesondere, wenn es sich um sessile gezahnte Adenome/Polypen (SSA/Ps) handelt: diese sind die geschädigten Vorläufer von circa einem von vier proximalen Kolorektalkarzinomen (Karzinome mit CpG-Insel-Methylierungs-Phänotypen (CIMP) sowie einer geschädigten DNA-mismatch Reparatur (MMR)). Dieses Projekt bezweckt die Entwicklung von molekularen Techniken, um eine bessere Identifikation der Vorläufer dieser CIMP-positiven, MMR-defizienten Karzinome neben den konventionelleren Methoden zu gewähren.
Lay summary

Wenn SSA/Ps die Vorläufer der CIMP-positiven Karzinome im proximalen Kolon sind, so kommen diesen vermutlich Eigenschaften zu, die den Progress dieser spezifischen Linie erleichtern und sie von deren Gegenstücken des distalen Kolons unterscheiden. Das hier vorliegende Projekt wurde entwickelt, um folgender Hypothese nachzugehen: Der Unterschied zwischen SSA/Ps des proximalen und distalen Kolons liegt in deren Niveaus an methylierten CpG-Inseln; ein epigenetisches Merkmal der DNA, welches die Genexpression reguliert. Um diese Hypothese zu testen werden wir die so genannte targeted multiplex Bisulfit-DNA-Sequenzierung anwenden und damit präinvasive Kolonläsionen mit sessiler und nicht-polypoider Morphologie (typisch für SSA/Ps), welche von 200 Patienten endoskopisch entfernt wurden, analysieren, um so epigenetische Veränderungen an 48 kürzlich von uns identifizierten genomischen Loci zu detektieren. Die Resultate werden im Lichte der high-throughput Studien der Cytosin-Methylierung und der Genexpression, welche mit DNA und RNA der lädierten Stellen von ausgewählten proximalen und distalen Kolon-SSA/Ps durchgeführt werden, verfeinert. Diese zweigleisige Herangehensweise sollte es uns ermöglichen, eine kleine Anzahl methylierter Promotoren sowie Gene mit veränderteren Expressionsmustern zu identifizieren und zu validieren. Die kombinierte Multiplexanalyse kann in ein simples molekulares Assay um-entwickelt werden, anhand dessen präkanzeröse Läsionen des proximalen Kolon, Vorläufer der CIMP-positiven, MMR-defizienten Karzinome, detektiert werden. Die molekulare Identifikation von Läsionen dieses Types – entfernt während einer Kolonoskopie – wird es den Klinikern ermöglichen, vermehrt rationale, kosteneffiziente endoskopische Überwachungen zu verschreiben. Zusätzlich sollte unsere genomweite Analyse der präkanzerösen Läsionen weitere Evidenz zu den den CIMP unterliegenden Ursachen in der Tumorigenese der Kolorektalkarzinome liefern.

Direct link to Lay Summary Last update: 21.04.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
The proto CpG island methylator phenotype of sessile serrated adenomas/polyps
Parker Hannah, OrjuelaStephany, Martinho OliveiraAndreia, CereattiFabrizio, SauterMatthias, HeinrichHenriette, TanziGiulia, WeberAchim, KomminothPaul, VavrickaStephan, AlbaneseLuca, BuffoliFederico, RobinsonMark, MarraGiancarlo (2018), The proto CpG island methylator phenotype of sessile serrated adenomas/polyps, in Epigenetics, 13(10-11), 1088-1105.
Targeted Proteomics for Multiplexed Verification of Markers of Colorectal Tumorigenesis.
Uzozie A., Selevsek N., Wahlander A., Nanni P., Grossmann J., Weber A., Buffoli F., Marra G. (2017), Targeted Proteomics for Multiplexed Verification of Markers of Colorectal Tumorigenesis., in Molecular and Cellular Proteomics, 16(3), 407-427.
The immune landscapes of polypoid and nonpolypoid precancerous colorectal lesions.
Maglietta A., Maglietta R., Staiano T., Bertoni R., Ancona N., Marra G.* (* equal contribution), Resta L.* (* equal contribution) (2016), The immune landscapes of polypoid and nonpolypoid precancerous colorectal lesions., in PLOS ONE, 11(7), 1-18.
Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A
Erzinger MM., Bovet C., Hecht KM., Senger S., Winiker P., Sobotzki N., Cristea S., Beerenwinkel N., Shay JW., Marra G., Wollscheid B., Sturla S. (2016), Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A, in PLOS ONE, 11(3):e0150219(11(3):e015), 1/17-17/17.
Metabolic alterations during colorectal cancer development - a combined analysis of the metabolome and transcriptome.
Fischer D. et al., Metabolic alterations during colorectal cancer development - a combined analysis of the metabolome and transcriptome., in manuscript in preparation, 0(0), 0-0.
Selected reaction monitoring for the verification of markers of colorectal tumorigenesis.
Uzozie A. et al., Selected reaction monitoring for the verification of markers of colorectal tumorigenesis., in Molecular and Cellular Proteomics, 0(00), 0-0.

Datasets

Transcriptomic and methylomic data

Author Marra, Giancarlo; Robinson, Mark
Persistent Identifier (PID) E-MTAB-6952; E-MTAB-6951; E-MTAB-6949.
Repository ArrayExpress
Abstract
Transcriptomic and methylomic data from RNA and DNA extracted from human colorectal tissues.

Collaboration

Group / person Country
Types of collaboration
Prof. Stephan Beck, Personal Genome Project UK, University College London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Mark Robinson, Institute of Molecular Life Science, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Dr. Paul Komminoth, Institute of Pathology, Triemli Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Susanne Ulbrich, Animal Physiology, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. Federico Buffoli, Gastroenterology Unit, Hospital of Cremona Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Achim Weber, Institute of Pathology, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. Primo Schär, Department of Biomedicine, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
PD Dr. med. Kaspar Truninger, Gastroenterologie Oberaargau Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof Dr. Stephan Vavricka, Gastroenterology and Hepatology, Triemli Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EMBL Conference Poster Identification of specific methylation targets of the serrated pathway to colon cancer. 03.05.2017 Heidelberg, Switzerland Marra Giancarlo; Parker Hannah;
Swiss meeting on genome stability and chromatin dynamics Poster The characterization of the serrated pathway to colon cancer 08.06.2016 Emmetten, Switzerland Marra Giancarlo; Parker Hannah;
EpiGeneSwiss meeting Poster The epigenome of serrated precancerous lesions of the large intestine. 06.06.2016 Weggis, Switzerland Marra Giancarlo;
6th Cancer Network Zurich retreat Poster The hypermethylator phenotype of sporadic colon cancers with defective mismatch repair. 25.04.2016 Emmetten, Switzerland Marra Giancarlo; Parker Hannah;
America Association Cancer Research (AACR) meeting Poster Benchmarking commercially available targeted bisulfite-sequencing platforms to gold-standard whole genome bisulfite sequencing. 16.04.2016 New Orleans, United States of America Parker Hannah;
Cancer Biology PhD Program retreat Poster The characterization of the serrated pathway to colon cancer 29.03.2016 Davos, Switzerland Marra Giancarlo; Parker Hannah;


Associated projects

Number Title Start Funding scheme
136247 Systems-wide responses of colon cells to food components and impact on cancer drug action 01.01.2012 Sinergia
179477 Road-mapping the serrated pathway of colon tumorigenesis: Step 2: Impact on clinical management of precancerous colorectal lesions. 01.05.2018 Project funding (Div. I-III)
141225 Identification of investment-worthy biomarker candidates for early diagnosis of colorectal tumors 01.05.2012 Project funding (Div. I-III)
122186 Functional characterization of novel molecular alterations identified in human colon tumors through transcriptomics and metabolomics 01.11.2008 Project funding (Div. I-III)

Abstract

Prevention of colorectal cancer has been greatly facilitated by the introduction of colonoscopy, which allows direct inspection of the gut’s epithelial lining and removal of any precancerous lesions that might be present. Ongoing advances in endoscopic technology, technique, and operator training have markedly reduced the incidence of colon cancers-at least in the distal colon. The more limited success achieved in the prevention of proximal colon cancers has been attributed in part to the higher prevalence in this portion of the large bowel of “flat” precancerous lesions, which develop laterally rather than protruding into the gut lumen like classical colon polyps. These lesions are not only more difficult to identify and excise during endoscopy: they are also more likely to be erroneously dismissed by pathologists as lesions with no malignant potential, and the patients harboring them followed with a relatively relaxed schedule of colonoscopic surveillance. The error can have grave consequences because flat lesions of this kind are typical of the recently recognized serrated pathway to colorectal cancer, and the subtype known as sessile serrated adenomas/polyps (SSA/Ps) are the putative precursors of a subset of proximal colon cancers characterized by the CpG-island methylator phenotype (CIMP) and defective DNA mismatch repair (MMR). CIMP is an epigenetic disorder of unknown origin, which can inactivate the transcription of tumor suppressors and other key genes by causing cytosine methylation in promoter CpG islands. Silencing of the MMR gene MLH1-a major CIMP target- occurs during the adenoma-carcinoma transition and leads to a typical DNA mutator phenotype. CIMP-positive / MMR-deficient colon cancers are sporadic (i.e., not inherited) and more common in older individuals, women in particular. They represent ~10% of all colorectal cancers and roughly one out of four of those in the proximal colon.If SSA/Ps are indeed the precursors of these cancers, proximal-colon SSA/Ps probably have features that facilitate this specific line of progression and distinguish them from their counterparts in the distal colon. The project described in this application is designed to test the hypothesis that the difference between proximal- and distal-colon SSA/Ps lies in their levels of CpG-island methylation. To this end, preinvasive colon lesions with sessile and nonpolypoid morphologies (typical of SSA/Ps) endoscopically removed from 200 women will be subjected to targeted multiplex bisulfite DNA sequencing to detect epigenetic and genetic alterations at 48 genomic loci, including 46 that have recently been identified by the PI’s group as likely targets of the “proto-CIMP” suspected to characterize proximal SSA/Ps. The results will be refined in light of the results of high-throughput assessment of cytosine methylation and gene expression studies conducted with lesional DNA and RNA from selected proximal- and distal-colon SSA/Ps. This two-pronged approach should allow us to identify and validate a small number of methylated promoters and genes with altered expression, whose combined, multiplexed analysis might be developed into a simple molecular assay for pinpointing precancerous proximal-colon lesions that are the actual precursors of CIMP positive / MMR-deficient cancers. Molecular-based identification of lesions of this type removed during colonoscopy will allow clinicians to prescribe more rational, cost-effective endoscopic surveillance. In addition, our genome-wide analysis of these precancerous lesions-in the absence of the “noise” caused by the myriad cancer-associated genetic alterations that occur later (MMR deficiency in particular)-should provide potential clues to the underlying causes of CIMP in colon tumorigenesis.
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