Project

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Susceptibility for cutaneous squamous cell carcinoma in organ transplant recipients

English title Susceptibility for cutaneous squamous cell carcinoma in organ transplant recipients
Applicant Hofbauer Günther Franz Ludger
Number 163369
Funding scheme Project funding (special)
Research institution Dermatologische Klinik Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Cancer Research
Start/End 01.01.2016 - 30.09.2019
Approved amount 587'583.00
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All Disciplines (4)

Discipline
Experimental Cancer Research
Cancer
Clinical Cancer Research
Dermatology

Keywords (9)

methylome; squamous cell carcinoma; cancer treatment; organ transplant recipients; RNA sequencing; polymorphisms; epigenetics; skin cancer; large nested project (STCS)

Lay Summary (German)

Lead
Hautkrebs ist eine häufige Folgeerkrankung bei Empfängern solider Organtransplantierte. Wir wissen, dass die Medikamente, die eine Abstossung unterdrücken, auch Krebsentstehung begünstigen. Unklar ist jedoch, warum einige Transplantierte mehr als andere von Hautkrebs betroffen sind. Dieses Projekt möchte die zugrundeliegenden Auslöser erkennen.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Auf der Ebene der Erbsubstanz DNS werden Mutationen und andere Abweichungen gesucht. Wir werden die Auswirkung auf sogenannte Transkriptionsfaktoren, die Zellwachstum im Allgemeinen steuern, untersuchen. Gefundene Unterschiede werden in Zellkulturen auf ihre Wirkung auf Tumorentstehung getestet.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Organtransplantierte haben ein kostbares Gut, ein Organ eines Spenders, erhalten. Ihr Interesse und das Interesse der Allgemeinheit ist es, nach geglückter Transplantation diesen Zustand zu bewahren. Hautkrebs ist dabei ein oft zunehmendes Problem, das Beschwerden, Kosten und schliesslich auch Sterblichkeit verursacht, die verhinderbar sein könnten. Unser Projekt will Risikofaktoren für spätere Hautkrebsentstehung erkennen, die eine vorauseilende Behandlung erlauben könnten.

Direct link to Lay Summary Last update: 30.09.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
rs34567942 a Novel Susceptibility Single Nucleotide Polymorphism for Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients
Kuzmanov A, Qi W, Stenz N, Bochud P, Kutalik Z, Wojtowicz A, Hofbauer G (2019), rs34567942 a Novel Susceptibility Single Nucleotide Polymorphism for Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients, in Acta Dermato Venereologica, 0-0.

Collaboration

Group / person Country
Types of collaboration
Pierre-Yves Bochud and the Swiss Transplant Cohort Study Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
148512 Swiss Transplant Cohort Study 01.02.2014 Cohort Studies Large
177522 Swiss Transplant Cohort Study 01.02.2018 Cohort Studies Large

Abstract

Skin cancers and skin inflammations like eczema or psoriasis are common skin diseases. Among those, actinic keratoses (AKs) are intraepithelial lesions that develop on sun-exposed surfaces of the skin such as the face, scalp or lower arms. These lesions result from UV-induced alterations in the epidermal part of the skin, and more specifically in keratinocytes. AKs may develop into invasive squamous cell carcinoma of the skin (SCC) which is the second most common form of skin cancer worldwide. It is thus a major source of morbidity and cost overall. The incidence (number of new cases arising in a given period expressed as a rate per 100,000 persons per year) for SCC over the last 40 years is increasing at an impressive pace in Western European countries and particularly in Switzerland. Switzerland has the highest SCC incidence rate among all countries in mainland Europe. It has also the fastest increase from 14.2/100 000 person-years in 1978 to 28.9/100 000 person-years in 1997 and keeps increasing in numbers, both medically and economically.Some populations are at a greatly elevated risk for SCC of the skin. Organ transplant recipients (OTRs) achieve maintenance of their graft by immunosuppressive medication which suppresses transplant rejection. Calcineurin inhibition is the cornerstone of most immunosuppressive regimes. This success of modern transplantation medicine is, however, countered by an increased cancer risk in this population. SCC is the most frequent complication in organ transplant recipients at a risk increased 60- to 100-fold compared to the general population. SCC in OTR is characterized by a higher risk of metastasis in up to 20% of cases and shows a more aggressive course than SCC in the general population. Not infrequently, successfully transplanted patients suffer a great burden in their quality of life and sometimes even a vital threat by the formation of SCC. The commonly used calcineurin inhibitor, cyclosporine A (CsA), directly induces tumor growth in murine models and in humans via transcription factor ATF3 and increases the secretion of transforming growth factor-ß and vascular endothelia growth factor conductive to SCC formation. While some mechanisms for this greatly increased risk of squamous cell carcinoma of the skin have been elucidated, open questions remain. However, not all patients undergoing immunosuppressive treatment develop SCC, some are heavily affected, others hardly. Therefore, this project proposes to integrate transcriptome with epigenetic and functional analysis to understand genetic predisposition to cancer, with SCC in OTR as a focus. Generally, the possible role of genetic/epigenetic modifications of gene networks in SCC predisposition is largely unexplored. Thus, identifying patient- and tumor-specific differences will provide a comprehensive landscape of actionable targets. As a consequence, this expanding knowledge has implications for all aspects of cancer management, including prevention, screening, and treatment.We will address two main aims: 1)To test the hypothesis that different susceptibility of OTR patients to skin SCC is linked to different expression of genes with key regulatory function in keratinocytes and skin homeostasis.2)To assess in primary keratinocytes derived from OTRs the difference in their tumor forming/yielding capability in a manner that can be explained by different genetic and/or epigenetic control of key regulatory genes.
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