Annual report 2018

GROW School for Oncology and Developmental Biology

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Programme 1Prevention

Programme leader:Prof.dr. Matty Weijenberg

Programme 2Innovative Cancer

Diagnostics & Therapy

Programme leader:Dr. Marjolein Smidt

Programme 3Basic and Translational

Cancer Biology

Programme leader:Prof.dr. Marc Vooijs

Programme 4Reproductional and Perinatal Medicine

Programme leader:Prof.dr. Luc Zimmermann

Executive Board

Scientific Director: Prof.dr. Manon van

Engeland

Managing Director: Judith Doomen

Programme Leaders

Strategic Board

Selected GROW researchers

Research Board

Chair: Dr. A. Voogd

Talent Scout

Dr. Jan Theys

PhD coordinators

Dr. Ton HopmanProf.dr. Theo de Kok

School Council

Departments

Young Investigators PhD representatives

PrefaceIn 2018 GROW took stock and performed a self-evaluation over the years 2012-2017. We are pleased to report that the main output indicators, i.e. number of PhD theses, number of (top 10%) publications and amount of research funding are steadily increasing. An international external review committee assessed the quality, societal relevance and viability of the research performed in GROW as very good, excellent and good respectively.

We have welcomed Prof.dr. Chris Wild, who took over the TEFAF Oncology chair from Prof. dr Jan Hoeijmakers and updated us on the urgency of prevention and early detection of cancer.

We celebrated 10 years of TEFAF Oncology Chairs with a symposium for which the previous TEFAF chairs returned to Maastricht to discuss the latest accomplishments and future developments in cancer epidemiology, prevention, biology, diagnostics and therapy.

We said farewell to Prof.dr. Frans Ramaekers, who has served GROW as scientific director for nine years.

We are exploring strong collaborations with the Maastricht UMC+ Oncology Center and the Center for Reproductive Health.

GROW scientists will continue to improve diagnosis, survival rates and quality of life of patients with malignant disease, hereditary disorders and developmental problems thereby making a significant impact on society.

We will offer them a scientific environment where reliable, reproducible and FAIR research is the gold standard and where young researchers are being trained to become independent and critical professionals.

We hope you enjoy reading this annual report.

Prof.dr. Manon van EngelandScientific director GROW-School for Oncology and Developmental Biology

Preface

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Both the results on faecal genotoxicity and DNA-adducts suggest a phytochemical-induced preventive effect. Gene expression analysis and DNA methylation profiles measured in colonic biopsies from the participants pro-vided molecular mechanisms which may mechanistically support a preventive effect of the consumption of meat products that are low in nitrite and contain a mix of bioactive ingredients that contribute to a balanced diet.

Keypoints• Ourgrouprecentlydevelopednewmeatprocessing

technologiesthatallowsreplacementofnitriteaspreservativebynaturalantioxidants.

• Consumptionofthisnewclassofnitrite-replacedmeatproductsshowedlessmarkersofcolorectalcancerrisksthanconsumptionoftraditionallyprocessedmeatinadietaryinterventionstudy.

• Currently,thetranslationofthesefindingstothemeatprocessingindustryisongoing.

Societal impactThe PHYTOME project has resulted in the design of new meat processing technologies that allow the replacement of nitrite as preservative by natural antioxidants. A dietary intervention study demonstrated that after consumption of this new class of meat products, markers of colorectal cancer risk were reduced. These outcomes, including the recipes and technological procedures have been disseminated among members of the European Association of Meat processing Industry (CLITRAVI- Brussels). CLITRAVI represents about 13,000 companies (mainly SME’s) which together manufacture around

There is convincing evidence that the consumption of red and particularly processed meat is associated with cancer risk. More recently, the International Agency on Research on Cancer even classified ‘processed meat’ as carcinogenic to humans (Group 1 carcinogen), based on sufficient evidence in humans that the consumption of ‘processed meat’ causes colorectal cancer. It has been proposed that endogenously formed N-nitroso compounds (NOCs) are responsible for the link between red meat consumption and colorectal cancer risk.

In our group (Prof.dr. Theo de Kok, Toxicogenomics), we initiated the EU project PHYTOME, which aims to develop new meat processing technologies, resulting in meat products that have no or strongly reduced nitrite levels, a food additive that is known to stimulate the formation of NOCs. The new meat products are enriched with carefully selected biologically active compounds, so called phytochemicals, present in various natural plant extracts. Different types of biologically active compounds may exert their beneficial action via different mechanisms, including effects at the level of formation and kinetics of carcinogenic compounds in the colon, and at the level

13,5 Mio tonnes of meat products. Based on a tentative cost-benefit assessment, estimating the incidence and social cost of colon cancer due to nitrate in drinking water in the EU it has been calculated that the effect of reducing NOC exposure is likely to be substantial, both in terms of loss of healthy life years or quality of life and in terms of disease associated societal costs. This requires successful introduction of PHYTOME-based projects in the market, on which several of the consortium partners from meat processing industry are currently working.

Colorectal cancer risk prevention: Phytochemicals to reduce nitrite in meat products (PHYTOME)

Research Narratives

of cellular protection (activation of antioxidant mechanisms and DNA repair). The new meat products have been evaluated in a human dietary intervention study comparing the effects of traditional meat products with those of the new products. White meat was used as a reference diet as consumption of chicken and other poultry has not been linked to increased cancer risk and was also found not to stimulate the endogenous formation of carcinogenic compounds.

The study showed that faecal excretion of NOC was significantly increased after consumption of traditional processed meat as compared to white meat consumption, but that this increase could be effectively reduced by adding natural extracts to the meat products. Faecal genotoxicity measurements demonstrated that consumption of meat products increases the induction of DNA strand breaks in colonic cells as compared to white meat. DNA strand breaks were not higher when the PHYTOME meat products were consumed. Also, DNA-adduct levels were higher after consumption of conventional products as compared to white meat, but not after consuming the PHYTOME meat products.

Dr. Simone van Breda and Prof.dr. Theo de Kok

Research Narratives

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Basal Cell Carcinoma (BCC) is the most common cancer in the Netherlands with approximately 40,000 new patients each year. Although it seldom metastasizes, it can cause large wounds and damage of vital structures due to contiguous growth if left untreated. Most BCCs need to be surgically removed. In superficial BCCs, where tumor growth is fixed to the epidermis, however, a less invasive approach is usually sufficient. This non-invasive therapy used to be mainly Photodynamic therapy (PDT). PDT is based on the activation of a topically applied photosensitizer followed by illumination with light of an appropriate wavelength leading to apoptosis of the tumor cells. For superficial BCC, PDT treatment consists of two cycles with a one-week interval.

In the guideline Basal Cell Carcinoma of the Dutch society for Dermatology and Venereology in 2007, PDT was the preferred non-invasive treatment. However, both 5-fluorouracil cream (5FU) and imiquimod cream were proposed to be considered as an alternative treatment for this type of BCC. Imiquimod activates the immune system and 5FU is a chemical agent that interferes with DNA synthesis resulting in subsequent cell death. Patients apply both creams themselves at home. Although PDT is most commonly used, evidence that its effectiveness is higher compared to imiquimod and 5FU cream is lacking. That is why we (Dr. Nicole Kelleners-Smeets, Dermatology, and colleagues)

After publishing the one-year follow-up data, the group of Dr. Nicole Kelleners-Smeets published several other manuscripts on different aspects with data of the trial; e.g. Dr. Aimee Arits and Dr. Brigitte Essers investigated cost-effectiveness, Dr. Brigitte Essers performed the patient preferences study, Dr. Marieke Roozeboom identified determinants for treatment failure4 and long-term effectiveness was studied by Dr. Klara Mosterd and Dr. Maud Jansen.

Furthermore, two new, investigator driven, randomized trials were initiated evaluating imiquimod in treatment of nodular basal cell carcinoma and actinic keratosis with funding from industry and ZonMw.

Keypoints• Ourgroupdemonstratedthattopicalimiquimod

andfluorouracilisnon-inferiorandevensuperioroftheoldPDTstandardtherapyinsuperficialbasal-cellcarinomas(sBCC)

• ThisstudychangedtheoldtreatmentpolicyofsBCCsandnowstatesthepreferreduseoftopicalimiquimod.

• Currently,weareinvestigatingimiquimodtreatmentofnodularbasalcellcarcinomaandactinickeratosisinclinicaltrials.

Societal impactWith this project, we could change current BCC treatment guidelines, resulting in better treatment with better performance for superficial BCC patients. Additionally, health insurance companies adjusted their criteria for reimbursement of PDT, therewith restricting its use. While this is very beneficial for patients with superficial BCC, the results also stimulated us to investigate treatment potential of imiquimod in nodular BCC. This way we envision to help even more patients in the future.

started a randomized controlled trial, financed by ZonMw, to compare the therapy options and could change current BCC treatment policy. Briefly, a total of 601 patients was randomized. The proportion of the patients who were tumor-free at one-year follow-up was 72.8% for PDT, 83.4% for imiquimod cream, and 80.1% for 5FU cream. The difference between imiquimod and PDT was 10.6% [95% CI 1.5 to 19.5; p=0.021] and 7.3% [95% CI –1.9 to 16.5; p=0.120]) between 5FU and PDT. Both imiquimod and 5FU cream were cost-effective compared to PDT. We concluded that 5FU is not inferior and imiquimod is even superior to PDT for treatment of superficial BCC. Both, imiquimod and 5FU cream are cost-effective therapies compared to MAL-PDT.

These results, obtained by Dr. Aimée Arits who was super-vised by Dr. Nicole Kelleners-Smeets, were published in the Lancet Oncology and received a lot of media attention. The results of this trial led to the adjustment of the BCC guideline, that is currently stating that imiquimod is the most effective and 5FU is a very cost-effective treatment. PDT should only be considered in patients that are not able to apply a cream themselves or those who have a contra-indication for surgery. Health insurance companies also adjusted their criteria for reimbursement of PDT, therewith restricting its use.

Non-invasive treatment of superficial basal cell carcinoma: results of a randomized controlled trial.

Dr. Nicole Kelleners-Smeets and Dr. Klara Mosterd

Research Narratives

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Pulmonary neuroendocrine neoplasms (pNENs) represent 20% of lung cancers, subdivided into low grade pulmonary neuroendocrine tumors (pNETs), i.e typical carcinoids (1.8%) and atypical carcinoids (0.2%), and high grade neuroendocrine carcinoma’s (pNECs), i.e. large-cell neuroendocrine carcinomas (LCNEC) (3%) and small-cell lung carcinomas (SCLC) (15%). Currently, good markers for pNENs therapy-response and recurrence rate are not available, necessitating an extensive follow-up of all patients with pNETs for up to 10 years at the moment. Thus, pNENs, in general, are in need for optimal risk stratification at first diagnosis as well as additional effective therapies.

The research group of Prof.dr. Ernst-Jan Speel (Depart-ment of Pathology, GROW School for Oncology and Developmental Biology) in collaboration with Prof.dr. Anne-Marie Dingemans (Pulmonology) aims to identify new biomarkers for diagnosis, prognosis and therapy of pNETs, in close collaboration with Prof.dr. Frans Ramaekers (Molecular Cell Biology). In 2008, PhD student Dorian Swarts showed that classification of carcinoids according to the World Health Organization (WHO) is subject to high-interobserver variation and suffers from detrimental variation in diagnostic nomenclature, and that both loss of chromosome 11q, MEN1 mutations as well as loss of Menin expression was associated with a

poor prognosis. Furthermore, OTP and CD44 expression were identified to be highly sensitive in predicting disease-free survival and overall survival was significantly better compared to current WHO classification.

Application of OTP and CD44 IHC also led to a superior prediction of prognosis in patients without consensus carcinoid type diagnosis in a histopathological inter- observer study. Dorian received two ENETS prizes and the Vera Bonte Prize 2015. Based on these data and the work of PhD student Jules Derks (see below), a grant from the Dutch Cancer Society was received in 2017 to validate OTP and CD44 in a population-based study and to further investigate OTP’s role as a tumor suppressor and prognostic indicator. In June 2018 PhD student Laura Moonen started on this project. Currently, these markers are already prospectively applied to diagnose difficult lung carcinoid/LCNEC cases at the MUMC.

In 2013, Jules Derks started his PhD in the Pathology lab in collaboration with Prof.dr. Anne-Marie Dingemans, funded by GROW and by a grant from the Dutch Cancer Society. His research concerned the identification of biomarkers to diagnose LCNEC on small biopsies, as well as biomarkers that may guide systemic chemotherapy treatment of patients with metastatic LCNEC. Using available databases of the Dutch Cancer Registry (IKNL)

Identification of biomarkers for prognosis and therapy of lung neuroendocrine tumors

and the Pathological Anatomical National Automated Archive (PALGA), he evaluated diagnostic and treatment data of ± 1000 patients with LCNEC. Upon validation in original tumor material, additional biomarkers to improve the precision of LCNEC diagnosis on a biopsy have been proposed. Additionally, we could reveal RB1 as a novel marker for discriminating SCLC and NSCLC type LCNEC, which is currently being used in clinical practice at the MUMC. Jules received the best ENETS poster prize (2015), first prize science day Maastricht UMC+,the Lung Cancer award (Foundation Post-Academic Teaching), a short-term research fellowship (ERS/EMBO) to perform genomic analyses of LCNEC at the IARC in Lyon, F. In 2017 Jules defended his thesis cum laude and the thesis was awarded in 2018 by the Vera Bonte price.

Prof.dr. Ernst-Jan Speel and Prof.dr. Anne-Marie Dingemans

The improved diagnosis and identified prognostic and predictive biomarkers for pNENs from the above studies have been presented and discussed with national and European pathologists in special sessions at the NVVP and ECP congresses in 2017, at ESMO 2017 and as invited lecture at ELCC 2018 and BTOG 2018.Recently, other biomarker studies to guide new therapies for LCNEC have been initiated that will be part of a new PhD project on LCNEC9 (PhD student Bregtje Hermans, start July 2018). >>

Research Narratives

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For more than two decades, reproductive genetics and its flagship Preimplantation Genetic Testing (PGT) have been at the frontline of innovative research and outstanding clinical care at Maastricht UMC+.

Thanks to the pioneering work and unwavering commit-ment of Dutch PGT founding fathers and (former) GROW members Prof.dr. Joep Geraedts, Prof.dr. Hans Evers and Prof.dr. Guido de Wert, the Maastricht UMC+ has profiled itself as the PGT Centre par excellence and is still, to this day, in the unique position to be the only centre in the Netherlands that has a permit to perform PGT. It has engaged in a strategic alliance with PGT transport centres in Utrecht, Groningen and Amsterdam called “PGD the Netherlands”, to ensure national coverage of PGT treatment. Prof.dr. Christine de Die-Smulders, PI and member of the strategic board of GROW, professor in PGD, is the general coordinator and current chair of ‘PGD the Netherlands’. Recent PGT innovations include the concept of pre-implantation genetic haplotyping using next-generation sequencing, which enables comprehensive genetic analysis of embryonic DNA from single blastomeres or few cells from the trophectoderm (TE). To patients, this “one-fits-all” PGT protocol (brand-named OnePGT) means that we will be able to significantly reduce the PGT preparation time (from as long as 18 months down to

two or three months). Moreover, this diagnostic novelty will allow us to offer PGT to a group of patients (~10% of all intakes) that previously could not or not optimally be treated. As of 2019, an increasing proportion of our PGT cycles will be performed by OnePGT to ultimately cover the majority of PGT production in the Netherlands. On-going research to study the genome plasticity during the early stages of human development will in future further optimize service to our patients (personalised medicine) and increase PGT pregnancy rates. Since 2017, Maastricht UMC+ has been one of the three national centres for Non-Invasive Prenatal Testing (NIPT). The brand new and state-of-art NIPT analysis pipeline processes unprecedented quantities of prenatal samples (over 40.000 samples in 2 years). Due to success and confidence in the future, the Dutch ministry of Health has recently decided to extend the protected status of the three NIPT centers for a period of 2 years (TRIDENT 2 program).

Based on our longstanding experience with single cell analysis, we were able to develop a novel concept for NIPT for monogenic disorders, which will be introduced in the clinic in the coming years. >>

Preimplantation Genetic Testing (PGT) and Reproductive GeneticsKeypoints

• Ourgrouphasshownintra-andinterobservervariationinthediagnosisoflungcarcinoids

• Ourgrouphasidentifiednovelprognosticbiomarkersforlungcarcinoids:OTP,CD44expression

• OTPandCD44willbevalidatedonapopulation-basedseriesoflungcarcinoid

• Stainingof>_3neuroendocrinemarkersinthediagnosticworkupofundifferentiatedNSCLConbiopsyspecimenshasshowntoenableLCNECdetection

• OurgrouphasshownthatNSCLCtypeLCNECshouldbetreatedwithplatinum-gemcitabine/paclitaxel(NSCLCtype)resultinginbetteroutcome

• ChemotherapydecisionfortreatmentofLCNECshouldbebasedonRB1immunostaining

• ResultsonpNENshavebeenpresentedanddiscussedat(inter)nationalmeetings

Societal impactWe have successfully identified OTP and CD44 as biomarkers of disease-free survival in pNETs, which is currently being validated in prospective clinical trials to be implemented in diagnostic routine. Additionally, we revealed markers for the diagnosis for LCNEC in small biopsies and a novel marker for discrimination of SCLC vs. NSCLC type LCNEC, RB1. Partially these markers are already implemented at Maastricht UMC+ for specific diagnostic cases. Next to that, results on pNENs have been presented and discussed at (inter)national meetings and we were invited to give lectures at several international meetings. Additionally, we have attracted industrial interest in our biomarker research to forward the translation of the findings into patient-relevant routine diagnostics.

Research Narratives

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The reproductive genetic package is complemented by high-tech periconceptional care including (genetic) risk profiling, detection and prevention of implantation and other reproductive dysfunctions as well as embryonal and foetal growth disorders and tailor-made interventions. Amongst others, we have developed and implemented a comprehensive test for Preconception Carrier Screening (PCS) based on whole exome sequencing that is unique in the Netherlands. The first results are promising and the test uptake by patients and referrers is high.

Given its leading PGT position, the Maastricht PGT Centre has a strong and charismatic appearance and is not only of great value to the patient, but also to both commercial and scientific partners. The commercial interest is shown by recent joint ventures with leading companies in the Life Sciences, resulting in novel applications for existing PGT technologies and even the development of new PGT technologies that are being used worldwide. Scientific collaborations comprise, amongst others, the national partnership with transport PGT centers and international partnership with the University of Brussels and the University Hospital Strasbourg.

Prof.dr. Christine de

Die-Smulders and

Dr. Edith Coonen

Keypoints• MaastrichtUMC+hasprofileditselfasthePre-

implantationGeneticTesting(PGT)CentreparexcellenceandhasengagedinastrategicalliancewithPGTtransportcentresinUtrecht,GroningenandAmsterdamcalled“PGDtheNetherlands”.

• MaastrichtUMC+isoneofthethreenationalcentresforNon-InvasivePrenatalTesting(NIPT).

• WehavedevelopedandimplementedacomprehensivetestforPreconceptionCarrierScreening(PCS)basedonwholeexomesequencingthatisuniqueintheNetherlands.

Societal impactBy virtue of its nature, PGT has the constant attention of both politicians and the lay public. We are regular and valued partners for politicians and advisory councils where the drafting of legislation and /or reports is concerned. On an international scale, Dr. Edith Coonen (GROW member and PI for Illumina, Agilent and Vitrolife projects) has contributed to a number of peer reviewed expert opinion papers on PGT, she is senior author of several peer reviewed international PGT guidelines and is a longtime member of the Genomics Quality Assessment (GenQA) External Quality Assessment (EQA) expert advisory board and assessor to a number of interna-tional PGT EQA schemes. Both Prof.dr. Christine de Die-Smulders and Dr. Edith Coonen are very committed to providing up-to-date information to and improving

communication with patients, students and health care professionals by means of oral presentations and digital media (website, patient tutorials, scientific webinars).

It is of utmost importance that PGT activities and out-comes are monitored, not just nationally but also on a European/global scale. To this end, the PGT Consortium of the European Society of Human Reproduction and Embryology (ESHRE) was set up. Like elsewhere, the Maastricht PGT Centre has contributed significantly to the functioning and success of this institution, by providing a founding steering committee member (Prof.dr. Joep Geraedts), a steering committee chair (Dr. Edith Coonen, 2015-2017, currently past chair) and several (first, last) authors to the many annual, peer re-viewed, PGT data publications. As of June 2019, Dr. Edith Coonen will be member of the ESHRE Executive Board.

Research Narratives

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Facts & Figures 2018

45 PhD theses

260 registered

PhD candidates

€ 6.980.211 contract value new projects

537 scientific

publications

60,5 fte employees

Facts & Figures 2018

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March 15

TEFAF Masterclass ‘The Exposome and Cancer Prevention’ and TEFAF Honorary Chair 2018 Inauguration ‘Two-way translational cancer research; an impetus for prevention, early detection and treatment’ of Prof.dr. Christopher P. Wild, Director International Agency for Research on Cancer (IARC).

June 22

TEFAF Oncology Summit ‘The Future of Cancer Management’10 years of TEFAF Oncology Chairs, we celebrated with a special symposium and former TEFAF Honorary Chair professors.

July 6

Farewell Prof.dr. Frans Ramaekers, Scientific director GROW 2010-2018valedictory lecture titled ‘KernGezond!!’

January 12

College Tour ‘Shaping your Career in Biomedical Sciences’with Prof.dr. Jan Hoeijmakers, Honorary Professor of the TEFAF Oncology Chair 2017, former chair of the Molecular Genetics department Erasmus MC Rotterdam.

Main events 2018

November 22

GROW Annual Science Day ‘The FAIRytale of Future Science’with keynote speaker Dr. Erik Schultes, GO FAIR International Support and Coordination Office and at the Human Genetics Department LUMC.

Main events 2018

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Training & EducationPartnerships

An important aim within GROW is the training of master- and PhD students in the fields of modern medicine and molecular life sciences. Therefore, we annually organize master classes and symposia for master and PhD students, postdocs and senior staff to update their skills and competences, to broaden their academic view, and to increase awareness with respect to research ethics and integrity.

Scientists at GROW collaborate closely with clinicians at the Maastricht UMC+ Oncology Centre (the future Maastricht Comprehensive Cancer Centre; Maastricht CCC), and at the future Centre for Reproductive Health (EVA).

TEFAFFive4FiveHealth Foundation LimburgKankeronderzoeksfonds LimburgKinderonderzoeksfonds LimburgMaastro ClinicOncoZon

Partnerships / Training & Education

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GROW School for Oncology and Developmental Biology Universiteitssingel 406229 ER, MaastrichtThe Netherlands

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@GROW.UM @GROW_UM