Dissecting the role of tumor-infiltrating clonal hematopoiesis in patients with gastrointestinal carcinomas

Principal Investigator

Scientific interest within the context of the graduate college:

The scientific focus of our lab centers on unraveling the multifaceted role of clonal hematopoiesis (CH) in disease prevention and inflammatory processes. CH is recognized as a pre-malignant condition that significantly increases the risk of hematologic malignancies. Beyond its oncogenic potential, CH has emerged as a critical risk factor for cardiovascular diseases such as stroke, myocardial infarction, and atherosclerosis, contributing to both initial and recurrent events. Moreover, CH is intricately linked to chronic inflammation, functioning both as a driver and a consequence of sustained immune dysregulation. By investigating these complex interconnections, our research aims to deepen the understanding of CH as a central node in disease pathogenesis and to identify novel strategies for early intervention and prevention.

Project description:

Clonal hematopoiesis (CH), defined by the acquisition of somatic mutations in hematopoietic stem cells, occurs in 20% to 30% of individuals >60 years. CH is associated with a higher overall mortality and an approximately 10-fold risk for the development of hematologic malignancies.¹ Reduced overall survival in individuals with CH is mainly caused by an increased rate of cardiovascular events.² A causal relation was found in preclinical models, showing accelerated development of atherosclerosis driven by an altered function of the NLRP3/IL1β inflammasome of mutated monocytes/macrophages.³ These results pinpoint toward pleiotropic effects of mutated clones, not only affecting self-renewal and differentiation of hematopoietic stem cells but also inflammatory signaling of mature blood cells.

In patients with solid cancer, a very recent report provided evidence that mutated CH-clones can infiltrate solid cancers in up to 30% of patients and remodel the tumor microenvironment and regulate malignant progression. This phenomenon is termed tumor-infiltrating CH (TI-CH).⁴ While the discovery of TI-CH sets the stage for an entirely new concept of oncogenesis and our understanding for respective tumor cell-microenvironment-interactions, thorough studies in clearly defined patient cohorts – preferentially treated within clinical trials – is warranted to understand how TI-CH may alter response to therapies, cytotoxic side-effects, disease recurrence and patients’ outcome.

The Damm lab has well-documented expertise in investigating CH in large-patient cohorts and has established the entire wet- and dry-lab pipelines to successfully conduct such complex experiments.^5,6 In close collaboration with the leading study group AG FIRE (Prof. Modest & Prof. Stintzing, Charité), we will investigate paired tumor and blood samples from more than 750 patients with gastrointestinal cancers. All patients were treated within prospective clinical phase 2 and 3 trials ensuring highest quality of clinical data and direct availability of respective patient specimen.

Aim 1: Defining the prevalence of CH and TI-CH in gastrointestinal cancer. Approximately 750 paired tumor and blood samples from patients with pancreatic cancer (PDAC) and metastatic colorectal cancer (mCRC) treated within prospective clinical phase 2 (PanaMa⁷) and phase 3 trials (CONKO-5⁸, FIRE-4⁹) will be analyzed for the presence of CH and TI-CH. Error-corrected target sequencing comprising 45 CH-associated genes will be performed using a fully established and automated workflow. CH mutations will be called using our in-house variant calling pipeline as recently published.¹⁰

Aim 2: Identification of CH and TI-CH related clinical phenotypes. Next, we will use the obtained genomic results from aim 1 and couple them with patients’ clinical characteristics. To this end, statistical analyses in uni- and multivariable models will be performed using the unique datasets within the clinical trials including primary and secondary study endpoints, but also benefitting from the extensive adjacent translational research projects which will offer discovery of unprecedent (e.g. already existing whole-transcriptome and mutation data, cfDNA).

Application details

References