Cancer Prevention Graduate School

Full project title: Prostate Cancer Prevention Clinic for Men with Risk of Familial Prostate Cancer (ProFam-Risk)

Principal Investigator / Doctoral Researcher: Peter Albers, Maike Klett
Institution: Düsseldorf University Hospital
Division: Department of Urology
Working group: Clinical Institute for Psychosomatic Medicine and Psychotherapy

Prostate cancer (PCA) is common in men. The life-time risk to develop PCA is estimated to be 11% and increases with BRCA2 or HOXB13 germline mutations up to 10-fold. Risk prediction includes a combination of germline genetic analysis with clinical parameters and imaging. The Prostate Cancer Prevention Clinic for men with familial risk will be a unique and first of its kind outpatient clinic which offers specialized diagnostics as a combination of multiparametric MRI, psychometric tests, and genetic analysis to establish an individualized risk score with consecutive risk-adapted monitoring. Men with family history or already known BRCA1 or BRCA2 mutation and their family members will be offered a combined clinical, imaging and genetic profiling to tailor their risk to develop PCA. In addition, men with prostate cancer and positive family history will be offered genetic testing and mutational profiling of tumor tissue in order to exclude or detect hereditary cancer syndromes. There are limited insights in the psychosocial consequences and behavioral outcomes of such testing. General recommendations for risk-communication (like for breast or ovarian cancer in women) will be adapted to male needs for PCa.
The aims and methods of the current application are to: (1) define a clinical pathway for invitation, screening, pre-test coaching, risk assessment and post-test coaching/counseling with risk stratification and recommendations for follow up visits; (2) develop and implement a training for urologists in risk communication for F- and H-PCa; (3) build up a prospective cohort for future research to validate the known genetic risk scores but also to follow different risk populations over time and investigate longitudinal genetic developments like epigenetic changes during the time of development of PCa; (4) survey the men with different risk profiles of F- and H-PCa with measures on prostate-specific anxiety, personal control and risk perception and other psychosocial outcomes to understand the psychosocial consequences of risk assessment and genetic coaching/counseling for different risk groups and to identify relevant factors (like age, socio economic status).

1. Russo J, Giri VN. Germline testing and genetic counselling in prostate cancer. Nat Rev Urol 2022. DOI: 10.1038/s41585-022-00580-7.
2. Giri VN, Knudsen KE, Kelly WK, et al. Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019. J Clin Oncol 2020;38(24):2798-2811. DOI: 10.1200/JCO.20.00046.Castro E, Mikropoulos C, Bancroft EK, et al. The PROFILE Feasibility Study: Targeted Screening of Men With a Family History of Prostate Cancer. Oncologist 2016;21(6):716-22. DOI: 10.1634/theoncologist.2015-0336.

Contact for further information
Prof. Dr. Peter Albers, peter.albers@med.uni-duesseldorf.de, +49 211 811 811 0
Dr. André Karger, andre.karger@med.uni-duesseldorf.de, +49 211-81 18 33 8

Full project title: Colorectal cancer screening in Germany – achievements and potential for improvement

Principal Investigator / Doctoral Researcher: Prof. Dr. Hermann Brenner, Dmitry Sergeev
Institution: German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
Division: Clinical Epidemiology and Aging Research

Colorectal cancer is the second most common cause of cancer related deaths in Germany. It still accounts for approximately 25,000 deaths each year, despite existence and offers of effective screening options. A large proportion of these deaths could be prevented by improvements in quality, implementation and use of screening offers. In this project, achievements of existing screening programs will be quantified (in terms of prevented cases, prevented deaths and prevented years of life lost) based on epidemiological evidence and modelling approaches. Comprehensive modelling analyses using validated Markov models developed by the hosting group will be performed to model expected future colorectal cancer incidence and mortality with the current screening offers and their use, and to explore and quantify the potential of enhancing effectiveness and cost-effectiveness of colorectal cancer screening by a variety of approaches. These may include enhanced screening tests (including novel biomarkers and novel imaging techniques, such as Artificial Intelligence assisted endoscopy), enhanced screening offers (such as optimized age ranges, screening and surveillance intervals, possibly also including risk-adapted offers and target group specific offers), enhanced screening invitation schemes and information approaches. The project will take advantage of comprehensive data and biobanks of large-scale population-based and screening cohorts and randomized trials conducted in the hosting group, comprehensive validated modeling programs developed by the supervisors, and established collaborations with multiple international partners and health insurance plans (1-5).

1. Guo F, Chen C, Holleczek B, Schöttker B, Hoffmeister M, Brenner H. Strong reduction of colorectal cancer incidence and mortality after screening colonoscopy: prospective cohort study from Germany. Am J Gastroenterol 2021;116:967-975.
   https://pubmed.ncbi.nlm.nih.gov/33929378/
2. Cardoso R, Guo F, Heisser T, ..., Ryzhov A, Hoffmeister M, Brenner H. Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: an international population-based study. Lancet Oncol 2021;22:1002-1013. https://pubmed.ncbi.nlm.nih.gov/34048685/
3. Cardoso R, Guo F, Heisser T, ..., Chirlaque MD, Hoffmeister M, Brenner H. Proportion and stage distribution of screen-detected and non-screen-detected colorectal cancer in nine European countries: an international, population-based study. Lancet Gastroenterol Hepatol 2022;7:711-723. https://pubmed.ncbi.nlm.nih.gov/35561739/
4. Heisser T, Hoffmeister M, Tillmanns H, Brenner H. Impact of demographic changes and screening colonoscopy on long-term projection of incident colorectal cancer cases in Germany: A modelling study. Lancet Reg Health Eur 2022;20:100451.
   https://pubmed.ncbi.nlm.nih.gov/35799615/
5. Guo F, Weigl K, Carr PR, Heisser T, Jansen L, Knebel P, Chang-Claude J, Hoffmeister M, Brenner H. Use of Polygenic Risk Scores to Select Screening Intervals After Negative Findings From Colonoscopy. Clin Gastroenterol Hepatol 2020;18:2742-2751.
   https://pubmed.ncbi.nlm.nih.gov/32376506/ 

Contact for further information
Prof. Dr. Hermann Brenner, h.brenner@dkfz.de, +49 6221-421300

Full project title: Analysis of risk factors for ETV6-RUNX1-positive childhood leukemia and translation into preventive measures and interventions

Principal Investigator / Doctoral Researcher: Ute Fischer, Dr. rer. nat., Ersen Kameri
Institution: University Clinic Düsseldorf, Heinrich-Heine-University Düsseldorf
Division: Department of Pediatric Oncology, Hematology and Clinical Immunology
Working group: Acquired predisposition to leukemia

The t(12;21) translocation encoding the fusion gene ETV6-RUNX1 characterizes the most frequent form of childhood leukemia. ETV6-RUNX1+ acute lymphoblastic leukemia (ALL) is associated with a prolonged, subclinical preleukemia starting in utero in 5% of healthy newborns and leading to leukemia in ~1 in 500 of those cases. Factors influencing the generation of preleukemic cell clones and their progression to leukemia are still largely unclear. ETV6-RUNX1+ ALL is associated with a good prognosis, but the disease is traumatic for children and families, the treatment is toxic and associated with life long side effects (cognitive defects, depression, sterility). The relapse rate is high (20%). Here, we propose to develop preventive strategies by targeting the disease at the preleukemic state.
In the proposed project cord blood samples of newborn cohorts will be characterized regarding individual genetic predisposition to childhood leukemia, immune system function and genotoxic exposure. Collected data of parents on life style, socioeconomic and educational status, diet, exposure to carcinogens and laboratory data on microbiome composition, nutrimetabolomics, and epigenomics will be analyzed to identify risk factors of childhood ETV6-RUNX1+ ALL. Knowledge, perceptions, and barriers (e.g. social disadvantages) of parents will be analyzed and adapted ways to communicate information on childhood leukemia and preventive measures will be developed (e.g. personal information or internet and social media platforms). A feedback system (e.g. short questionnaires) will be developed and used to check on suitability and gain of knowledge.
The proposed study aims to elucidate the interplay of genetic predisposition, lifestyle, host and environmental factors regarding their impact on leukemogenesis in children. It aims to identify risk factors and to test new communication tools for informing future parents about childhood leukemia and preventive measures.

1. Toward prevention of childhood ALL by early-life immune training. Hauer J, Fischer U, Borkhardt A. Blood. 2021 Oct 21;138(16):1412-1428.
2. An intact gut microbiome protects genetically predisposed mice against leukemia. Vicente-Dueñas C*§, Janssen S*§, Oldenburg M*, Auer F, González-Herrero I, Casado-García A, Isidro-Hernández M, Raboso-Gallego J, Westhoff P, Pandyra AA, Hein D, Gössling KL, Alonso-López D, De Las Rivas J, Bhatia S, García Criado FJ, García Cenador MB, Weber APM, Köhrer K, Hauer J, Fischer U*§, Sánchez-García I*§, Borkhardt A*§. Blood 2020;136:2003-2017.
3. The preleukemic TCF3-PBX1 gene fusion can be generated in utero and is present in ≈0.6% of healthy newborns. Hein D, Dreisig K, Metzler M, Izraeli S, Schmiegelow K, Borkhardt A, Fischer U§. Blood 2019;134:1355-1358.
4. Five percent of healthy newborns have an ETV6-RUNX1 fusion as revealed by DNA-based GIPFEL screening. Schäfer D, Olsen M, Lähnemann D, Stanulla M, Slany R, Schmiegelow K, Borkhardt A, Fischer U§. Blood 2018; 131: 821-826.
5. Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Fischer U*, Forster M*, Rinaldi A*, Risch T*, Sungalee S*, Warnatz H-J*, Bornhauser B, Gombert M, Kratsch C, Stütz AM, Sultan M, Tchinda J, Worth CL, Amstislavskiy V, Badarinarayan N, Baruchel A, Bartram T, Basso G, Canpolat C, Cario G, Cavé H, Dakaj D, Delorenzi M, Dobay MP, Eckert C, Ellinghaus E, Eugster S, Frismantas V, Ginzel S, Haas O, Heidenreich O, Hemmrich-Stanisak G, Hezaveh K, Höll JI, Hornhardt S, Husemann P, Kachroo P, Kratz CP, te Kronnie G, Marovca B, Niggli F, McHardy AC, Moorman AV, Panzer-Grümayer R, Petersen BS, Raeder B, Ralser M, Rosenstiel P, Schäfer D, Schrappe M, Schreiber S, Schütte M, Stade B, Thiele R, von der Weid N, Vora A, Zaliova M, Zhang L, Zichner T, Zimmermann M, Lehrach H, Borkhardt A, Bourquin J-P, Franke A, Korbel JO, Stanulla M, Yaspo M-L. Nature Genet 2015;47:1020-1029.

Contact for further information
Dr. Ute Fischer, Ute.Fischer@med.uni-duesseldorf.de, +49 211 811-6339

Full project title: Discovery and validation of biomarkers for ovarian cancer earlier detection

Principal Investigator / Doctoral Researcher:  Renée Turzanski Fortner, Ph.D., Victoria Cooley
Institution: German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
Division: Cancer Epidemiology
Working group: Hormones and Cancer

Ovarian cancer is a lethal disease, frequently diagnosed at late stage after the disease has spread. Current strategies for screening use a combination of blood-based biomarkers, notably CA125, and ultrasound. However, this method has insufficient sensitivity and specificity for the detection of early-stage cancers. This has motivated a continued search for complementary biomarkers to improve early detection, with the ultimate goal of improving survival.

The PhD student will lead studies investigating blood-based biomarkers for ovarian cancer early detection in large prospective cohort studies such as the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and the PREDICT early detection consortium. These studies will be conducted in study participants with blood samples collected up to years prior to diagnosis, plus cancer-free controls. The evaluation of pre-diagnosis samples will allow a detailed estimation of the diagnostic discrimination by time between blood collection and diagnosis, toward understanding the earlier detection potential. The project will investigate pathways such as microRNAs and tumor-associated autoantibodies, estimating the potential of promising markers on these pathways for improved discrimination beyond the current standard CA125.

1. Terry KL, et al. A prospective evaluation of early detection biomarkers for ovarian cancer in the European EPIC cohort. Clinical cancer research 2016
2. Fortner RT, et al. Ovarian cancer early detection by circulating CA125 in the context of anti-CA125 autoantibody levels: Results from the EPIC cohort. International journal of cancer 2018;142(7):1355-60
3. Fortner RT, et al. Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort. Journal of ovarian research 2017;10(1):20
4. Elias KM, et al. Diagnostic potential for a serum miRNA neural network for detection of ovarian cancer. Elife 2017;6
5. Kaaks R, et al. Tumor-associated autoantibodies as early detection markers for ovarian cancer? A prospective evaluation. International journal of cancer 2018;143(3):515-26

Contact for further information
Dr. Renée Turzanski Fortner, r.fortner@dkfz.de 

Full project title: Mutation analysis for hematologic and cardiologic risk management in patients with clonal hematopoiesis of indeterminate potential (CHIP)

Principal Investigator / Doctoral Researcher: Prof. Dr. Ulrich Germing, Anna Maria Cacic
Institution: Heinrich-Heine-University Düsseldorf, University Hospital Düsseldorf
Division: Dept. of Hematology, Oncology & Clinical Immunology

Acquired genetic mutations in hematopoietic stem cells can lead to clonal expansion and imbalanced blood cell production. Clonal hematopoiesis is common with human aging, confers a risk of evolution to hematologic malignancies (hazard ratio 10), and increases all-cause mortality and the risk of cardiovascular disease (HR 2). The degree of risk appears to depend on the specific mutant allele driving clonal expansion, number of mutations, mutant allele burden, and concomitant nongenetic risk factors. A dominant clone can contribute to vascular events by proinflammatory and proatherogenic interactions with endothelium, and can worsen heart failure by altering myocardial remodeling. CHIP can progress to myelodysplastic syndromes (MDS) or leukemias. The Düsseldorf MDS Registry is one of the largest MDS data bases, including a MDS biobank. We will use a 40-gene NGS panel to identify patients with CHIP who may be prone to develop MDS and/or cardiovascular complications. This will include patients with germline mutations in the BRCA1/2 cancer predisposition genes who seem to be particularly prone to develop clonal hematopoiesis after chemotherapy or treatment with PARP inhibitors. The gene panel will also cover 20 genes that can harbour germ line mutations predisposing to myeloid malignancies. Machine learning will be used to correlate the clinical course with patterns of mutational clonal evolution, harnessing cytomorphologic, histopathologic, and chromosomal data. We will implement a joint (hematology & cardiology) clinic for identifying and counseling patients with CHIP. This will include training of staff in genetic counseling for risk-assessment and implementation and evaluation of a user-friendly digital tool for patient information and gathering of patient-reported outcome measures.

1. Jaiswal S, et al: Clonal hematopoiesis in human aging and disease. Science. 2019 Nov 1;366(6465)
2. Jaiswal S, et al.: Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med. 2017 Jul 13;377(2):111-121.

Contact for further information
Norbert Gattermann, gattermann@med.uni-duesseldorf.de, +49 211-81-17720

Full project title: Testing the effectiveness of a social prescription and virtual patient information in increasing tertiary prevention among cancer patients

Principal Investigator / Doctoral Researcher: Prof. Dr. Anne Herrmann-Johns, Lisa Boyer
Institution: University of Regensburg
Division: Department of Epidemiology and Preventive Medicine
Working group: Medical Sociology

Tertiary prevention through physical activity and psychosocial support can improve a number of outcomes for cancer patients, including improved overall quality of life, lower risk of cancer recurrence and improved cancer survival. However, adoption rates of programmes designed to increase tertiary prevention among cancer patients remain low. A number of strategies have been developed to increase preventive health behaviour, including social prescriptions, which provide individualised care plans to refer patients to nonclinical services to enhance patients' physical and mental health. However, further evidence is required on which strategies are most effective in increasing preventive health behaviour of cancer patients and should thus be used in clinical practice. Also, support persons have been shown to facilitate patients' engagement in preventive health behavior but their role in helping cancer patients become physically active and seek further supportive care remains understudied. Support persons often suffer themselves from low quality of life and require additional support to address their owns needs and concerns. This project will use a multidisciplinary approach to test the effectiveness of a social prescription and virtual patient information in increasing the uptake of physical activity and participation in social activities and psychosocial support among cancer patients and support persons. It will further establish whether the interventions can improve patients' and support persons' outcomes. Cost-effectiveness and implementation barriers and enablers of the interventions will also be explored to help translate evidence into practice. Thus, this project will employ innovative methodology using an effectiveness-implementation hybrid design and a mixed-methods approach to identify effective strategies and assess which strategies could be best used in routine cancer care. These strategies could be made accessible, sustainably integrated into practice functioning and thus allow for widespread adoption to help provide optimal cancer care and enhance an active lifestyle among cancer patients and their support persons.

Contact for further information
Prof. Dr. Anne Herrmann-Johns, anne.herrmann@klinik.uni-regensburg.de, +49 941 944 5231

Full project title: Development and evaluation of a novel biomarker panel for early detection of lung cancer and personalized intervention strategies

Principal Investigator/ Doctoral Researchers: Prof. Thomas Kindler, Juliane Griesbach and Timm Winkelmeier
Institution: University Medical Center Mainz
Division: University Cancer Center Mainz

Early detection of cancer and, at its best, combined to early intervention, represents one of the great challenges of medicine and is an important pillar for early intervention. Novel techniques such as circulating tumor (ct)DNA analysis and plasma protein profiling provide unique opportunities to detect cancer at early stages across tumor entities.

The primary goal of this project is to identify alterations of plasma protein patterns predictive for lung cancer in otherwise asymptomatic patients. We will take advantage of a well-established mouse model for lung cancer which closely mimicks human lung cancer initiation and progression. This allows us to track tumor development and its influence on systemic alterations over time. Serial blood samples will be analysed using high-multiplex, high-throughput targeted immuno-PCR based proteomics. Identified signatures will be compared to those of lung cancer patients at different stages. The proteomic profile will further be evaluated for shared and specific protein patterns in a cohort of individuals free of lung cancer at the time of blood sampling with incident lung cancer during the follow-up. Comprehensive data from the population-based Gutenberg Health Study are available. Complementarily, the targeted proteomics approach will be expanded by examining 258 additional proteins associated with cancer and inflammation in the subjects with cancer and matched controls. This will generate a proteomic signature associated with incident lung cancer using state-of-the-art biostatistics and machine learning methods. By comparing protein patterns and involved pathways between settings in animal models and humans, a bidirectional translational approach with forward and backward translation will help test transferability and assess clinical relevance. Protein signatures will be further analyzed to unravel shared pathomechanisms across disease, linking pathophysiology between cancer and cardiovascular disease. Finally, results of this project will facilitate to prepare a prospective, longitudinal screening study to identify individuals at increased risk for developing lung cancer.

1. Hähnel PS, Enders B, Sasca D, Roos WP, Kaina B, Bullinger L, Theobald M, Kindler T. (2014) Targeting components of the alternative NHEJ pathway sensitizes KRAS mutant leukemic cells to chemotherapy. Blood 123, 2355-2366.
2. Rosigkeit S, Kruchem M, Thies D, Kreft A, Eichler E, Boegel S, et al. (2021) Definitive evidence for Club cells as progenitors for mutant Kras/Trp53-deficient lung cancer. Int J Cancer. 2021 Jul 31. doi: 10.1002/ijc.33756.
3. Wild, P.S., et al. [The Gutenberg Health Study]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 55, 824-829 (2012).
4. Ten Cate V, Koeck T, Prochaska J, et al. A targeted proteomics investigation of the obesity paradox in venous thromboembolism. Blood Adv. 2021;5(14):2909-2918. doi:10.1182/bloodadvances.2020003800
5. Ten Cate V, Prochaska JH, Schulz A, et al. Protein expression profiling suggests relevance of noncanonical pathways in isolated pulmonary embolism. Blood. 2021;137(19):2681-2693. doi:10.1182/blood.2019004571

Contact for further information
Patricia Hähnel, haehnpa@uni-mainz.de, +49 6131 179727

Full project title: Polygenic Risk Score for a population-based risk adapted breast cancer screening – implementation and evaluation of consequences

Principal Investigator / Doctoral Researcher: PD Dr. med. Anne Quante, Sidra Rashid
Institution: Gynaecological Clinic, Technical University of Munich, Germany, University Hospital rechts der Isar
Division: Gynecological Tumor Genetics

Breast cancer is the most common cancer in women (1). Women at the age 50 to 69 are biannually invited for the mammography-screening program (MSP). The aim of MSP is the early detection of breast cancer to reduce breast cancer mortality. There has been a lot of controversy about efficacy of MSP since the expected reduction of mortality is low and the number of unnecessary diagnostic procedures is high (2, 3).
Recently updated German guidelines state that for women younger than 50 and older than 70 "screening decisions based on individual risk" should be considered, and recommend screening women ages 40-49 who are at "moderate BC risk". These recommendations acknowledge that the current age-based eligibility criteria for MSP for a woman from the general population do not account for other well-established breast cancer risk factors, e.g. a woman's BC family history, lifestyle factors and polygenic risk score (4).
In this public health and communication research focused project the candidate will compare the current age-based screening strategy to risk-based screening strategies. The candidate will have access to the KORA survey. The KORA study following 18,000 people in southern Germany provides Information on lifestyle, reproduction, diet and disease history. KORA also provides valuable data on family ancestry and SNP markers (GSA array) for a subpopulation of its participants. In addition, the candidate will develop a questionnaire and address medical professionals. Medical professionals working in the field of risk-adapted screening need to understand risk assessment through statistical models to adequately provide counselling to their patients. (5) The aim is develop a tool to support counselling for risk-adapted screening.

1. Quante AS, Ming C, Rottmann M, Engel J, Boeck S, Heinemann V, et al. Projections of cancer incidence and cancer-related deaths in Germany by 2020 and 2030. Cancer Med. 2016;5(9):2649-56.
2. Quante AS, Husing A, Chang-Claude J, Kiechle M, Kaaks R, Pfeiffer RM. Estimating the breast cancer burden in Germany and implications for risk-based screening. Cancer Prevention Research. 2021;Manuscript accepted.
3. Friedewald SM. Breast Cancer Screening: The Debate that Never Ends. Cancer treatment and research. 2018;173:31-8.
4. Quante AS, Whittemore AS, Shriver T, Strauch K, Terry MB. Breast cancer risk assessment across the risk continuum: genetic and nongenetic risk factors contributing to differential model performance. Breast cancer research: BCR. 2012;14(6):R144.
5. Furst N, Kiechle M, Strahwald B, Quante AS. Mammography Screening 2.0 - How Can Risk-Adapted Screening be Implemented in Clinical Practice?: Results of a Focus Group Discussion with Experts in the RISIKOLOTSE.DE Project. Geburtshilfe Frauenheilkd. 2018;78(5):506-11.

Contact for further information
PD Dr. med. Anne Quante, anne.quante@mri.tum.de, +49 89 4140 2420

Full project title: Preventing Esophageal Cancer – Combined Analysis of epidemiological, microenvironmental and molecular risk factors in a cohort of Barrett Esophagus patients

Principal Investigator / Doctoral Researchers: Michael Quante, Prof. Dr. med., Linus R. Schoemig and Susann Schütte
Institution: Medical Center University of Freiburg
Division: Center of Medicine
Working Group: Gastrointestinal Oncology Lab, M Quante

Barrett's esophagus (BE), the pre-malignant condition to esophageal adenocarcinoma (EAC) is an exemplary system to longitudinally study the evolution of malignancy. The incidence of BE has increased tremendously over the last several decades, resulting in a large number of individuals "at risk" for this very lethal malignancy. Thus, there is a critical need to develop preventive strategies. In a young and innovative research group at the Medical Center of the University of Freiburg we aim in exploiting the tempo-spatial dynamics of BE combining public health and social factors with biological measurements of the microenvironment and epithelial compartment to identify prognostic tools. For that we will utilize our unique prospective BE patient registry (BarrettNET, >900 patients) including tissue biopsies, stool and saliva samples, blood samples and epidemiologic surveys with a long term follow up (9 years) and work together with our multiple national and international collaborators. Our goal for two graduate projects is to provide a collaborative and integrated combination of epidemiologic (PhD I) and molecular (PhD II) biomarker or risk factors to develop and tailor a risk prediction model for BE.

Project part 1: In the public health and epidemiology focused graduate project the candidate will analyze the structured epidemiologic questionnaire, obtaining information on demographics, lifestyle factors and health of all patients and identify specific risk factors within those patients that progress to cancer vs those who did not. The comprehensive epidemiologic questionnaire and the prospective design of the BarrettNET will allow to detect non-genetic risk factors associated with the progression from BE to EAC. This will include analysis of stool and saliva samples by 16s microbiome sequencing and correlation with nutrition data. In close collaboration with the partnering graduate project an integration of epidemiological, microbiome and molecular data should be performed. Ultimately, the vision is to translate personalized risk assessment into improved prevention by focusing screening efforts on those individuals who are most likely to develop cancer.

Project part 2: The goal of this graduate project will be to identify novel biomarker by sequencing biopsy material during disease progression in order to discover potential expression changes that predict progression. Besides the epidemiological evaluation we aim to put special emphasis on the role of the tumor microenvironment during early esophageal carcinogenesis. To understand the relationship between epithelial cells and immune and mesenchymal stromal cells we will perform multi-parameter single-cell protein analysis by mass cytometry (CyTOF) in combination with RNA sequencing of epithelial and stromal compartments after laser capture microdissection. This detailed cell-based evaluation of BE tissue of progressors versus that of non-progressors during disease development will allow a temporal-spatial analysis of potential molecular factors that drive inflammation induced cancer.

A close collaboration of the graduate students will be necessary to achieve these goals and will provide a unique collaboration of epidemiological/puplic health and basic science teams.

1. Quante, M., T.C. Wang, and A.J. Bass, Adenocarcinoma of the oesophagus: is it gastric cancer? Gut, 2022.
2. Kunze, B., F. Wein, H.Y. Fang, A. Anand, T. Baumeister, J. Strangmann, S. Gerland, J. Ingermann, N.S. Munch, M. Wiethaler, V. Sahm, A.H. Sastre, S. Lange, C.J. Lightdale, A. Bokhari, G.W. Falk, R.A. Friedman, G.G. Ginsberg, P.G. Iyer, Z. Jin, H. Nakagawa, C.J. Shawber, T. Nguyen, W.J. Raab, P. Dalerba, A.K. Rustgi, A.R. Sepulveda, K.K. Wang, R.M. Schmid, T.C. Wang, J.A. Abrams, and M. Quante, Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma. Gastroenterology, 2020.
3. Schmidt, M., D.P. Ankerst, Y. Chen, M. Wiethaler, J. Slotta-Huspenina, K.F. Becker, J. Horstmann, F. Kohlmayer, A. Lehmann, B. Linkohr, K. Strauch, R.M. Schmid, A.S. Quante, and M. Quante, Epidemiological risk factors in a comparison of a Barrett Esophagus Registry (BarretNET) and a case control population in Germany. Cancer Prev Res (Phila), 2020.
4. Munch, N.S., H.Y. Fang, J. Ingermann, H.C. Maurer, A. Anand, V. Kellner, V. Sahm, M. Wiethaler, T. Baumeister, F. Wein, H. Einwachter, F. Bolze, M. Klingenspor, D. Haller, M. Kavanagh, J. Lysaght, R. Friedman, A.J. Dannenberg, M. Pollak, P.R. Holt, S. Muthupalani, J.G. Fox, M.T. Whary, Y. Lee, T.Y. Ren, R. Elliot, R. Fitzgerald, K. Steiger, R.M. Schmid, T.C. Wang, and M. Quante, High-fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via IL8 and Alterations to the Gut Microbiome. Gastroenterology, 2019.
5. Wiethaler, M., J. Slotta-Huspenina, A. Brandtner, J. Horstmann, F. Wein, T. Baumeister, N. Radani, S. Gerland, A. Anand, S. Lange, M. Schmidt, K.-P. Janssen, A. Conrad, W. Johannes, K. Strauch, A.S. Quante, B. Linkohr, K.A. Kuhn, R. Blaser, A. Lehmann, F. Kohlmayer, W. Weichert, R.M. Schmid, K.-F. Becker, and M. Quante, BarrettNET—a prospective registry for risk estimation of patients with Barrett's esophagus to progress to adenocarcinoma. Diseases of the Esophagus, 2019.
6. Quante, M., T.A. Graham, and M. Jansen, Insights into the Pathophysiology of Esophageal Adenocarcinoma. Gastroenterology, 2017.
7. Quante, M., G. Bhagat, J.A. Abrams, F. Marache, P. Good, M.D. Lee, Y. Lee, R. Friedman, S. Asfaha, Z. Dubeykovskaya, U. Mahmood, J.L. Figueiredo, J. Kitajewski, C. Shawber, C.J. Lightdale, A.K. Rustgi, and T.C. Wang, Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell, 2012. 21(1): p. 36-51.

Contact for further information
Sekretariat Prof. Dr. Michael Quante, Kirstin Schneider, kirstin.schneider@uniklinik-freiburg.de, +49 761 270- 32768

Full project title: Cancer literacy as an essential factor for lifestyle behavior changes: An observational and interventional study (CLARO study)

Principal Investigator / Doctoral Researcher: Prof. Dr. Karen Steindorf, Mona Illmann
Institution: German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
Division: Physical Activity, Prevention, and Cancer

A healthy lifestyle could prevent more than 40% of incident cancer cases (Global Burden of Disease Study, 2022). To raise awareness of the importance of a healthy lifestyle for reducing the risk of cancer, people need to know what behaviors are associated with cancer risk as well as how to find and understand reliable sources of information. This knowledge and the related skills are described by the concept of cancer literacy (Diviani and Schulz, 2011). This study will be the first to examine cancer literacy for cancer prevention in a representative adult study population (N = 800) in Germany. The findings will provide valuable insights into the state of knowledge regarding cancer prevention and enable the identification of sociodemographic groups with particularly low levels of cancer literacy.

The study will further set up a web-based randomized intervention to effectively improve cancer literacy on prevention behaviors. Previous research has shown limited awareness of lifestyle behaviors, such as physical inactivity or poor diet, as risk factors for cancer (Shahab, McGowan et al., 2018). This seems to be related to the belief that one's cancer risk cannot be influenced by behavior choices but is determined by non-modifiable factors (Fleary, Paasche-Orlow et al., 2019). Information on the modifiability of the individual cancer risk will be presented using different health communication strategies with varying modalities (textual vs. audiovisual) and modes of communication (formal vs. narrative). An audiovisual modality and a narrative mode of communication are promising approaches of health communication for changing cancer literacy (De Looper, Damman et al., 2020). Overall, insights of the study will allow the implementation of future interventions that link to current knowledge on cancer prevention in Germany and effectively target the belief that cancer risks are modifiable.

Contact for further information
Dr. Alexander Haussmann, alexander.haussman@nct-heidelberg.de, +49 6221-422383

Full project title: Smoke-free environments in pregnancy and early life: a life-course approach to cancer prevention interventions for disadvantaged families

Principal Investigator / Doctoral Researcher: Prof. Dr. Hajo Zeeb, MSc, Bibiana Cristina Barrera Bernal
Institution: Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen
Division: Department of Prevention and Evaluation
Working group: Research unit Social Epidemiology

In a life-course perspective, pregnancy and birth of a child are opportune moments for smoking cessation. While a considerable proportion of (expecting) parents alter their smoking behaviour during this period, this is less the case in socially disadvantaged families. The increasing population diversity and the neglected role fathers can play in creating smoke-free environments call for migrant- and gender-sensitive approaches to quit or reduce smoking in this period. This project aims 1) to review the evidence of migrant and gender sensitive approaches to reduce smoking during pregnancy and the first years of life among socially and culturally diverse families, 2) to co-design an intervention with stakeholders and sociocultural diverse families, and 3) to assess the feasibility of this intervention in a mixed-methods design.

Aim 1 will be achieved by a systematic literature review. Based on this, an intervention for smoking reduction using a co-design process approach and exploring the potential for integrating digital elements will be developed (Aim 2). Finally, the intervention will be delivered by midwives to socially disadvantaged families who either take part in the Pro Kind home visiting programme or visit a large communal midwifery center. The feasibility of the intervention will be assessed in a controlled before-after design using a matched control group. Maternal smoking will be assessed as primary outcome, paternal smoking and the children's exposure to second-hand smoke as secondary outcomes. Focus group discussions will assess the appropriateness and the applicability of the intervention in other settings of early childhood interventions (Aim 3).

The project will provide new insight into how smoke-free environments are negotiated and achieved in socially and culturally diverse families. It will explore innovative communication formats and participatory approaches when designing the intervention.

1. Tönnies T, Pohlabeln H, Eichler M, Zeeb H, Brand T. Relative and absolute socioeconomic inequality in smoking: time trends in Germany from 1995 to 2013. Ann Epidemiol. 2021; 53:89-94.e2.
2. Schoenaker D, Ploubidis GB, Goodman A, Mishra GD. Factors across the life course predict women's change in smoking behaviour during pregnancy and in midlife: results from the National Child Development Study. Journal of epidemiology and community health. 2017;71(12):1137-44
3. Wehby GL, Prater K, McCarthy AM, Castilla EE, Murray JC. The Impact of Maternal Smoking during Pregnancy on Early Child Neurodevelopment. J Hum Cap. 2011;5(2):207-54.
4. Samkange-Zeeb F, Borisova L, Padilla B, Bradby H, Phillimore J, Zeeb H, et al. Superdiversity, migration and use of internet-based health information – results of a cross-sectional survey conducted in 4 European countries. BMC Public Health. 2020;20(1):1263.
5. Sierau S, Dähne V, Brand T, Kurtz V, von Klitzing K, Jungmann T. Effects of Home Visitation on Maternal Competencies, Family Environment, and Child Development: a Randomized Controlled Trial. Prev Sci. 2016;17(1):40-51

Contact for further information
Dr. Tilman Brand, brand@leibniz-bips.de, +49 421 218 56917