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Road-mapping the serrated pathway of colon tumorigenesis: Step 2: Impact on clinical management of precancerous colorectal lesions.

English title Road-mapping the serrated pathway of colon tumorigenesis: Step 2: Impact on clinical management of precancerous colorectal lesions.
Applicant Marra Giancarlo
Number 179477
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 01.05.2018 - 30.04.2022
Approved amount 443'723.00
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All Disciplines (2)

Discipline
Molecular Biology
Clinical Cancer Research

Keywords (5)

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

Lay Summary (Italian)

Lead
La via "serrata" della tumorigenesi colorettale: Impatto sulla gestione clinica delle lesioni precancerose del colonretto.Parole chiave: colonretto; lesioni serrate sessili; adenomi; epigenoma; espressione genica; diagnosi molecolare(Maggiori dettagli nell'Abstract in Inglese - For more details, see Abstract in English)
Lay summary

Decenni di prevenzione tramite colonscopia ci hanno fornito una stima affidabile del rischio di cancro rappresentato dagli adenomi colorettali, generalmente chiamati polipi. Si conosce meno il potenziale tumorigenico delle lesioni precancerose "serrate", così chiamate per le tipiche pieghe del loro epitelio di superficie. Particolarmente importanti sono le lesioni serrate sessili, ovvero non polipoidi, ma piatte. Esse rappresentano solo il ~5% di tutti i tumori colorettali precancerosi, ma sembrano dare origine a ~20% di tutti i cancri colorettali, in particolare quelli con un fenotipo "metilatore" (ovvero, con abbondante metilazione del DNA in specifiche regioni genomiche che regolano l'espressione dei geni). Rispetto agli adenomi, le lesioni serrate sessili sono più difficilmente identificabili durante colonscopia, in parte per la loro posizione prevalente nel colon prossimale e in parte perche' piatte, con bordi mal definiti e colore simile a quello della mucosa normale. Inoltre, la loro diagnosi istologica è caratterizzata da variabilità tra gli esaminatori, il che significa che quelle rimosse durante la colonscopia possono essere classificate erroneamente.

In questo studio intendiamo impiegare, per applicazioni cliniche, l'enorme quantita' di dati "omici" (genomici, epigenomici, trascrittomici, proteomici e metabolomici) ottenuti in laboratorio usando biopsie endoscopiche colorettali. Siamo ora in grado di tracciare la rete dei processi molecolari la cui disregolazione promuove la tumorigenesi serrata. Altrettanto importante, siamo pronti a verificare i risultati su ulteriori campioni di tessuto umano, un passo necessario verso la loro applicazione in ambito clinico.

Numerosi loci genetici ipermetilati sono attualmente in fase di verifica come promettenti biomarcatori per la diagnosi precoce, pre-colonoscopica, dei tumori colorettali (dal DNA estratto dalle feci). Abbiamo anche individuato diversi fattori di trascrizione e proteine della membrana cellulare che sono espressi esclusivamente in lesioni serrate. Questi saranno testati per la loro capacità di migliorare la diagnosi istologica differenziale delle lesioni colorettali precancerose e la gestione clinica dei pazienti predisposti a cancro colorettale.

Direct link to Lay Summary Last update: 05.04.2018

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
DAMEfinder: a method to detect differential allele-specific methylation
Orjuela Stephany, Machlab Dania, Menigatti Mirco, Marra Giancarlo, Robinson Mark D. (2020), DAMEfinder: a method to detect differential allele-specific methylation, in Epigenetics & Chromatin, 13(1), 25-25.
The DNA hypermethylation phenotype of colorectal cancer liver metastases resembles that of the primary colorectal cancers
Orjuela Stephany, Menigatti Mirco, Schraml Peter, Kambakamba Patryk, Robinson Mark D., Marra Giancarlo (2020), The DNA hypermethylation phenotype of colorectal cancer liver metastases resembles that of the primary colorectal cancers, in BMC Cancer, 20(1), 290-290.
Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice.
Ragusa Simone, Marra Giancarlo (2020), Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice., in Journal of Clinical Investigation, (10.1172/JC), 1-18.

Associated projects

Number Title Start Funding scheme
160163 Road-mapping the serrated pathway of colon tumorigenesis: Step 1: Epigenetic profiling of precancerous, proximal-colon lesions in women. 01.05.2015 Project funding (Div. I-III)

Abstract

Decades of screening colonoscopy data have provided us with a reliable estimate of the cancer risk posed by conventional colorectal adenomas. Less is known about the more recently defined "serrated" precancerous lesions, so called because of the saw-tooth-like epithelial infolding found in their crypt lumens. Sessile serrated adenomas/polyps (SSA/Ps) are of particular interest. They represent only ~5% of all precancerous colorectal tumors but appear to give rise to ~20% of all colorectal cancers-that is, a distinct subset of sporadic, proximal colon cancers with a CpG island methylator phenotype (CIMP) and in most cases, DNA mismatch repair (MMR) deficiency. Compared with conventional adenomas, SSA/Ps are easier to miss during endoscopy, owing in part to their prevalent location in the proximal colon and in part to their morphology. They are nearly always flat or sessile lesions with poorly defined borders and color resembling that of the normal mucosa. In addition, pathologic diagnosis of serrated lesions is characterized by inter-examiner variability, which means that SSA/Ps removed during colonoscopy are likely to be misclassified. Our hypothesis is that proximal-colon SSA/Ps are at least as dangerous as conventional adenomas.The distinctive biology of this type of precancerous lesions hold answers to many of our questions, but our knowledge of the molecular processes driving SSA/P development is limited. In 2015, we initiated an SNF-funded project to fill this gap. Step 1 involved investigation of the epigenetic and transcriptional landscapes of SSA/Ps, and it generated a rich body of multiomics data that is now ready for analysis. Our main objectives now in Step 2 are to identify molecular processes that are SSA/P-specific and to exploit this knowledge to develop clinical tools that will improve the diagnosis and management of these lesions. Comprehensive analysis of our omics data from precancerous serrated tumors-in the absence of the “noise” caused by the myriad genetic alterations that occur after transformation has taken place (MMR deficiency in particular)-should provide a clear picture of the events driving serrated tumorigenesis.Working with a bioinformatics group, we will develop a new bioinformatic method that will allow more accurate and reliable integrative analysis of epigenomic and gene-expression data. With this and other computational methods, we will identify the signaling pathways and molecular networks essential for SSA/P development. SSA/P-specific changes detected in this phase of the project will then be verified in a large series of serrated and non-serrated lesions to vet their potential as diagnostic or predictive biomarkers. Candidates identified thus far include genetic loci displaying SSA/P-specific DNA hypermethylation, which could be used in assays for early, non-invasive diagnosis of these lesions, as well as transcription factors and cell-membrane proteins, whose identification could improve their differential diagnosis during endoscopy and histological examination. Verification studies (already authorized by 3 local ethics committees) will include tissue chromatin immunoprecipitation, pyrosequencing, in situ hybridization, and immunohistochemistry. They will yield a short-list of investment-worthy candidate markers, which can be clinically tested in the future (Step 3) to validate their ability to improve the management of SSA/Ps and increase our chances of preventing proximal colon cancers. Upon completion of Step 2, coincident with my retirement, the tissue and nucleic acid samples collected by my lab, with the wealth of data we have generated, will be transferred to the Swiss Epigenetic Colorectal Cancer Cohort study biobank, where they can be used for future studies.
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