INDICATE Initiative: Two papers on the topic of HLA type, cancer risk and cancer immunoediting are published this month in the International Journal of Cancer and HLA

Mathematics in Oncology
© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control

The associations of certain HLA types with disease susceptibility have been previously shown for virus infections, however in cancer this aspect remains poorly understood. Lynch syndrome with its genetically defined population and strong involvement of the immune system in the carcinogenic process is an ideal model to address this question for the first time in a systematic manner.

Our previous research pointed at a possible influence of the HLA type on the potential of the immune system to eliminate cancer cells. Together with our colleagues from DMQ (HITS) and our INDICATE partners from Germany, the United Kingdom, Finland, the Netherlands, Norway, and Hungary we now have published an open access article in the International Journal of Cancer, describing the fascinating interplay between the HLA system and human disease susceptibility, announcing the launch of INDICATE and inviting researchers worldwide to collaborate in this project.

Moreover, we developed a refined approach for characterizing presence or absence of HLA-A*02, the most common HLA-A allele in the Caucasian population, in archival samples, which is now published in HLA. By sharing this methods with our peers, we want to promote studying HLA type-dependency during the pathogenesis of a wide range of diseases and make archival and historic tissue samples accessible for identifying HLA-A*02 alleles.

March 22nd is the Global Lynch syndrome Awareness Day

Mathematics in Oncology

It’s Lynch Syndrome Day!

March 22nd is the Global Lynch syndrome Awareness Day. People with Lynch syndrome have a genetic predisposition to develop various types of cancer, particularly colon and uterine cancer, at a young age. There is an estimated number of around 300,000 Lynch syndrome carriers in Germany, however only about 5% of those have been diagnosed so far and therefore have the opportunity to participate at preventive and early detection measures in a timely manner.

The genetic changes underlying Lynch syndrome cannot be cured, but many types of cancer that can occur in the context of Lynch syndrome can, if detected early enough. The diagnosis of Lynch Syndrome also enables testing of family members for this hereditary predisposition and adaptation of preventive measures to the increased cancer risk at a young age.

Several clinical and molecular indications are important for the suspicion of Lynch syndrome:

  • early age at diagnosis, for example colon cancer or uterine cancer before the age of 50,
  • family history of gastrointestinal or gynecological cancer,
  • typical changes in the tumor tissue (evidence of microsatellite instability or evidence of failure of the mismatch repair genes)

Lynch Syndrome is still mainly unknown to the public today. And unlike many other European countries, not all colorectal cancer tumors are tested for the typical molecular changes in Germany today, and thus, the opportunity to discover the hereditary risk is being missed.

Lynch Syndrome Awareness Day was created to raise awareness of this hereditary cancer risk, so that more affected people can be diagnosed at an early stage and so that more of those affected can take part at specialized cancer surveillance programs.

Save the date: Lynch syndrome Patient Information Day on March, 12th

Mathematics in Oncology

Lynch syndrome Patient Information Day

Lynch patients are confronted with questions from different subject areas: What prevention and early detection do I need? How do I deal with the knowledge of lifelong cancer risks? What new findings are there in terms of diagnostics and therapy? Where can I find the right information and advice? Patient advocacy and support group Semi-Colon will discuss these and other questions together with Lynch syndrome families and exchange experiences in dealing with the hereditary cancer risk.

To this event several experts have been invited who will provide an overview of the main topic, inform about new findings and developments in Lynch syndrome / HNPCC and, of course, will also be available to answer the questions.

For more information please follow as well as Semi-Colon Facebook page.

Normal mucosa immune milieu in Lynch syndrome carriers and tumor patients: our new publication in Gastroenterology

Mathematics in Oncology

© Kloor / DKFZ

Colorectal immune microenvironment as a risk factor for colorectal cancer in Lynch syndrome

Lynch syndrome is the most common inherited colorectal cancer syndrome. However, only approximately half of variant carriers develop cancer during their life. Factors determining cancer risk in Lynch syndrome individuals are largely unknown. In our recent study published this month in Gastroenterology we analyzed normal colorectal mucosa of Lynch syndrome tumor patients and Lynch syndrome carriers without tumor manifestation as well as Lynch syndrome colorectal cancer tissue for immune cell composition. For that we used quantitative immune cell analysis by immunohistochemistry and expression profiling of more than 700 immune-relevant genes. Our results revealed drastic differences in the qualitative and quantitative immune cell composition of tumor tissue compared to normal mucosa samples. Importantly, among the normal mucosa samples, those from tumor-free Lynch syndrome carriers were clearly distinguished from normal mucosa samples of tumor patients. In addition, analysis of rectal mucosa samples from CAPP2 trial participants with long follow-up revealed that the density of T cells in the normal mucosa correlated with time to tumor manifestation in Lynch syndrome. Our study reflects an important role of the immune profile of normal colorectal mucosa in Lynch syndrome-associated tumorigenesis.

The study was mainly funded by the Else-Kröner-Fresenius-Foundation and conducted in cooperation with the Department of General Pathology, UKHD (Albrecht Stenzinger, Jan Budczies, Martina Kirchner and Klaus Kluck), University Hospital Bonn (Robert Hüneburg and Jacob Nattermann), NCT Heidelberg (Georg Martin Haag and Elena Busch), University of Newcastle, UK (John Burn and Richard Gallon), University of Jyväskylä, Finland (Jukka-Pekka Mecklin and Toni Seppälä) and other national and international collaborators.

New Research Project in Mathematical Oncology 

Mathematics in Oncology

Synergizing tumor biology and mathematics to decode tumor development in hereditary colon cancer using mathematical modelling of medical data 

ATB and EMCL have joined forces in a new research project funded by the Klaus Tschira Foundation. The aim of the collaborative project is to understand tumor initiation, evolution, and immunology by means of mathematical modeling and thereby find approaches to potentially prevent hereditary cancer in the future. The Heidelberg project entitled “Mathematics in Oncology” is a pilot initiative to strengthen interdisciplinary translational research. Through the three-year funding, the Klaus Tschira Foundation is supporting an interdisciplinary project that enables new synergies between mathematics and medicine and strengthens the innovative research profile of Heidelberg as a center of science.

ATB Alumnus Dr. Alexej Ballhausen receives AIO Young Scientist Award 2021

Mathematics in Oncology
Mathematics in Oncology
Dr. Alexej Ballhausen receives the AIO Young Scientist Award 2021 for his research on the role of immune selection in the evolution of MSI cancer published in Nature Communications.

AIO Young Scientist Award 2021

This year, the AIO (Arbeitsgemeinschaft Internistische Onkologie) in the German Cancer Society (Deutsche Krebsgesellschaft e. V.) is for the first time awarding the Young Scientist Award for innovative work in the field of medical oncology, including all topics related to pathogenesis, pathophysiology, diagnostic and prognostic factors as well as therapy and aftercare of malignant, solid tumors. This award serves to promote the next generation of scientists and oncologists.

The AIO Young Scientist Award goes to the author(s) with the best publication on the above-mentioned focuses. We are proud to announce that the AIO Young Scientist Award 2021 was received by our ATB Alumnus Alexej Ballhausen currently working at Charité , Berlin (Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology and Tumor Immunology). Alexej received the Award for the great contribution to unraveling the role of immune selection in the evolution of microsatellite-unstable cancers, which was published in Nature Communications 2020 (see also press-release of DKFZ, Heidelberg University Hospital and HITS, as well as Behind the paper Blog post by Matthias Kloor).

We thank the AIO for distinguishing Alexej’s scientific work, congratulate Alexej to this highly honorable Award and wish him lots of success in his future career!

PhD Student Position in Mathematics (f/m/d) at EMCL

Mathematics in Oncology


At the Engineering Mathematics and Computing Lab (EMCL) the following position is to be filled with 39.5h/week from December 1st, 2021 or as soon as possible thereafter:

PhD Student Position in Mathematics (f/m/d)

Project: Mathematical Oncology

Cancer is one of the leading causes of disease-related death worldwide. In recent years, rapid increase in the molecular understanding of cancer has unraveled significant additional complexity of the disease. Although large amounts of data on cancer genetics and molecular characteristics are available and accumulating with increasing speed, adequate interpretation of these data still represents a major bottleneck. This is exactly where mathematics can be applied to oncology: Through mathematical modeling of complex biological processes we are able to gain novel medical insights.

The project aim is three-fold: Firstly, mathematically modeling the evolution of hereditary tumors to improve the existing prevention strategies, secondly, elevating tumor immunology to a genome-wide level using adequate data analysis and modeling techniques, and thirdly, predicting the efficacy of clinical approaches for diagnostics, prevention and treatment based on the developed models.

The project will be supervised by Prof. Dr. Vincent Heuveline (EMCL) and PD Dr. Matthias Kloor (ATB). It is fully funded by Klaus Tschira Foundation Project “Mathematics in Oncology”. Remuneration is based on TV-L E 13. The position is fully funded for 3 years.

Immune prevention of inherited colorectal cancer

Mathematics in Oncology

© Kloor / DKFZ


Recurrent frameshift neoantigen vaccine elicits protective immunity with reduced tumor burden and improved overall survival in a Lynch syndrome mouse model

Lynch syndrome is the most common inherited colorectal cancer syndrome predisposing affected individuals to developing cancer at young age. Due to the distinctive character of tumor pathogenesis in Lynch syndrome and well-defined target population, Lynch syndrome represents both clinically and molecularly an ideal scenario for testing the feasibility of immune-preventive approaches against cancer. Our group has been studying the mutational and immune profile of Lynch syndrome-associated tumors for more than 20 years. This research led to identification of candidate neoantigens for a potential preventive vaccination in Lynch syndrome. The identified candidates have been tested for safety and immunogenicity in a Phase I-IIa clinical trial. The tumor-preventive effect of this vaccination strategy in humans needs to be demonstrated in future clinical trials. However, already now the success of this approach could be demonstrated in a Lynch syndrome mouse model. The results of this study were recently published in Gastroenterology.

The study on a Lynch syndrome mouse model for the first time demonstrates that tumor prevention by vaccination with mutation-induced neoantigens is feasible and effective. The immune prevention strategy by vaccination with selected neoantigens therefore holds great promise for individuals with Lynch syndrome. The study is the result of a long-lasting successful collaboration between the DKFZ (Heidelberg, Germany), Heidelberg University Hospital, Weill Cornell Medical College (New York, USA) and the National Cancer Institute (Bethesda, USA). The project was funded mainly by the NCI in frame of the Cancer Moonshot Program and the German Research Foundation (Deutsche Forschungsgemeinschaft).

Scientists from Heidelberg tackle early colorectal cancer formation using mathematical models

Mathematics in Oncology


Mathematical modeling of molecular pathways in colorectal carcinogenesis and colonic crypt evolution in Lynch syndrome

Two studies have been published recently in frame of the “Mathematics in Oncology” collaborative initiative between ATB and the Engineering Mathematics and Computing Lab (EMCL), Heidelberg University ( The first study published in PLOS Computational Biology delivers the results of a new mathematical model of colorectal carcinogenesis that consists of multiple components accounting for dependent and independent mutational events. The obtained simulation results are in concordance with current clinical tumor data, giving hints to the initial steps of cancer formation in Lynch syndrome. The approach provides a modular framework for modeling multiple pathways of carcinogenesis that could be applied to other organs by slight modifications.

In the second study published in Computational and Systems Oncology the scientists used computer simulations to analyze the biological processes behind the invisible initial steps of colon cancer development on a crypt level. Current research suggests that specific mutated crypts are the origin of colon cancer. Analyzing the mutational processes within a crypt is key for understanding cancer development and may have significant implications for cancer prevention. The scientists have now developed a computational model to simulate these mutational processes within a crypt on a computer. These computer simulations allow analyzing if and how fast different so-called driver mutations take over a crypt. The results of the study provide a valuable basis for future studies directed to support tailored management of Lynch syndrome carriers.

Anita- and Friedrich-Reutner-Prize 2020

MSI cancer evolution and immunoediting

Dr. Aysel Ahadova from the Department of Applied Tumor Biology, Institute of Pathology at Heidelberg University Hospital receives the Anita- and Friedrich-Reutner-Prize 2020 for her research on tumor prevention in Lynch Syndrome, the most common inherited colorectal cancer syndrome.–eierstock–und-brustkrebs/

Scientists Dr. Aysel Ahadova and Dr. Dr. Sabine Heublein awarded Anita- and Friedrich-Reutner-Prize 2020 

This year’s Anita-and-Friedrich-Reutner-Prize was awarded to two scientists for their excellent  contribution to individualized prevention and treatment of colorectal, breast and ovarian tumors.

Dr. Aysel Ahadova from ATB investigates carcinogenic pathways of the most common inherited colorectal cancer syndrome, Lynch syndrome, and their importance for the tailored design of cancer preventive measures.

With the yearly awarded prize of  10.000 Euro Professor Dr. Friedrich Reutner – Honorary Senator of the University Heidelberg – and his wife, Anita Reutner support female scientists of the Medical Faculty, with a particular focus on clinically relevant research questions.

LYNKED IN 2020 Conference at Dana Farber Cancer Institute: Keynote Speaker Matthias Kloor

MSI cancer evolution and immunoediting

2020 Lynch Syndrome Virtual Patient Conference

The 5th Annual LYNKED IN conference for individuals and families of those with Lynch syndrome was held on Saturday, September 12, 2020.

  • Over 750 attendees registered for the event from 39 states and 14 countries.
  • The conference brought together over 230 attendees in a live virtual series of talks and Q&A sessions.
  • Advocacy groups joined LYNKED IN this year in post-conference break-out rooms.

Matthias Kloor gave this years’ Keynote Lecture at the virtual LYNKED IN Conference and talked about the latest advances in vaccine development for Lynch syndrome-associated tumors. For watching this and other video presentations from LYNKED IN 2020 please click here.

Immune surveillance and immunoediting in microsatellite-unstable cancers: our new publication in Nature Communications

MSI cancer evolution and immunoediting


The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution

Cancer evolution recapitulates basic principles of biology in a nutshell, as surviving cell clones over time acquire mutations that allows them to thrive in an often hostile and changing environment. Adaptation processes leave their traces in the genome of manifest cancers, so studying cancer genomes can open a window into the past. In this sense, analyzing mutation signals in tumor genomes to unravel early steps of tumor formation shares similarities to cosmology research measuring cosmic microwave background noise to shed light on the origin and history of the universe.

The present study was a collaboration between the Heidelberg University Hospital, the DKFZ Heidelberg, Heidelberg University, the Heidelberg Institute for Theoretical Studies (HITS) and international collaboration partners. We developed ReFrame, a new algorithm to quantitatively detect microsatellite indel mutations with high sensitivity. Using ReFrame, we identified mutations shared by most MSI colorectal and endometrial cancers.

We further discovered a negative correlation between the prevalence of a defined indel mutation in MMR-deficient colorectal or endometrial cancers and the predicted immunogenicity of the resulting frameshift peptide. Our study strongly supports the concept of continuous immunoediting in human cancers and provides new evidence for the hypothesis that immunogenic cancers and pre-cancer cell clones can be attacked and potentially eradicated by the host’s immune system.

This strongly encourages the concept of neoantigen-based cancer-preventive vaccines that may in the future help to reduce tumor risk in Lynch syndrome and potentially beyond. We have recently demonstrated the safety and immunological efficacy of a prototype frameshift peptide vaccine in a phase I/IIa clinical trial.

New publication in the “Mathematics in Oncology” collaboration

cos efficacy of BRAF testing

© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control

Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics (doi: 10.1002/ijc.33273)

In frame of the “Mathematics in Oncology” collaborative initiative between ATB and the Engeneering Mathematics and Computing Lab (EMCL), Heidelberg University (, we aim to gain novel insights into cancer evolution through mathematical modeling of the underlying complex biological processes.
We focus on microsatellite-unstable (MSI) cancers, which show a high number of mutations due to a deficiency of the DNA mismatch repair system responsible for repairing mistakes occuring during DNA replication.

MSI cancers develop in elderly patients sporadically and in younger patients in the context of Lynch syndrome, the most common inherited colorectal cancer syndrome. Lynch syndrome is associated with an increased life time risk of developing cancer in the large bowel (colorectal cancer), the endometrium and other organs.

Lynch syndrome is estimated to affect 1 out of 280 individuals, yet often remains undiagnosed. Thus, a diagnostic procedure with high sensitivity and specificity is of central clinical significance. As BRAF V600E mutations have been reported to be associated with sporadic MSI cancers, current international diagnostic guidelines recommend using BRAF mutations in order to distinguish between sporadic and likely hereditary MSI colorectal cancer. Due to a significant difference in age at diagnosis between sporadic and hereditary MSI CRC patients, we hypothesized that the performance of BRAF testing for identifying sporadic MSI CRC could be age-dependent.
In our recent study, we systematically analyzed data from published studies, public databases and population-base patient cohorts. In addition, we performed sensitivity analysis as well as cost calculations of BRAF testing.
We identified that though being highly effective in older patients, BRAF testing led to a high risk of missing Lynch syndrome patients and increased costs at age <50 years, thereby showing its poor performance in this age group. We therefore suggest to directly refer MSI CRC patients <50 years to genetic counseling without BRAF testing.

The study was developed through the active Mathematics in Oncology collaboration (Link: with the Engeneering Mathematics and Computing Lab (EMCL, Head: Vincent Heuveline), Heidelberg University Hospital, together with the Department of General Pathology, Institute of Pathology, University Hospital Leipzig and various institutions of other German universities. Hendrik Bläker from the University Hospital Leipzig, Michael Hoffmeister from the Division of Clinical Epidemiology and Aging Research, DKFZ (German Cancer Research Center), Aysel Ahadova and Matthias Kloor, both from ATB (Head: Magnus von Knebel Doeberitz), designed the study, collected and analyzed data from different sources. From EMCL, Saskia Haupt and Vincent Heuveline were strongly involved in the analysis and interpretation of the data. The study titled “Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics” (doi: 10.1002/ijc.33273) was recently published in the International Journal of Cancer.

Molecular diversity of Lynch syndrome colorectal cancer reflected in clinical disease manifestation: an international study published in Gastroenterology

cos efficacy of BRAF testing

© Matthias Kloor

Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome. (doi: 10.1053/j.gastro.2019.12.032)

Lynch syndrome is the most common inherited colorectal cancer syndrome. The affected individuals carry a germline variant in one of the mismatch repair genes (MLH1, MSH2, MSH6 and PMS2), enhancing their lifetime risk of developing a broad spectrum of tumors, most commonly colorectal and endometrial cancer. In order to prevent colorectal cancer, colonoscopy with polypectomy is recommended for Lynch syndrome carriers. However, the reasons for colorectal cancer development under regular colonoscopy surveillance in some Lynch syndrome carriers are unknown.

In our previous study, we demonstrated the molecular diversity of Lynch syndrome-associated colorectal cancers, showing that different pathogenic pathways going through two distinct types of precursor lesions may lead to colorectal cancer in Lynch syndrome. In the present study, we, together with our collaboration partners from Germany, Finland and the Netherlands, were able to link the molecular diversity of Lynch syndrome colorectal cancer to the clinical picture of colorectal cancer (incidence of adenoma and colorectal cancer) under colonoscopy surveillance.

Our data demonstrate that the observed diversity is associated with the MMR gene affected in the germline, and suggest tailoring the preventive approaches for Lynch syndrome carriers according to pathogenic pathways dominating the carcinogenic process depending on the MMR gene.

The study was performed with grant support of Wilhelm Sander Foundation and German Cancer Aid.