Project Details
Projekt
Molecular evaluation and modeling of therapy associated polyposis
Applicant
Dr. Ann-Cathrine Berking
Subject Area
Human Genetics
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564693616
A subset of patients who receive treatment for childhood or young adult cancer (CYAC) and achieve remission develop colorectal polyposis decades later, a poorly defined syndrome called therapy-associated polyposis (TAP). The overall objective of this proposal is to elucidate the unknown genetic and epigenetic basis of TAP and to develop patient-derived organoids as a new model system for studying the molecular underpinnings of this condition. By understanding the causal mechanisms of TAP, this research seeks to identify patients at risk for TAP and subsequent colon cancer, ultimately enabling the development of effective clinical interventions, including improved surveillance and preventive strategies. We hypothesize that radiation and/or chemotherapy for CYAC leads to TAP via therapy-induced somatic variants that impact an undefined predisposing germline alteration in the coding or noncoding genome. Somatic variants consequently mediate loss of heterozygosity of a germline predisposition allele, triggering polyp formation and significantly increasing the risk of cancer. To evaluate our hypotheses, we propose three specific aims: (1) To define the molecular basis of TAP through genomic sequencing. By pursing comprehensive whole genome sequencing using novel methodology (i.e., long read sequencing) in multiple adenomas and paired normal colonic tissue from at least ten patients with TAP, we will reveal germline variants and clonal and sub-clonal somatic alterations. (2) To characterize epigenomic and transcriptional patterns of TAP at single cell resolution. To define precancer cell states and reveal conserved programs in colonic neoplasia, we will perform paired scRNA-seq and scATAC-seq on adenomas and paired normal tissue. By integrating single cell transcriptome and chromatin accessibility data, we will nominate regulators of neoplastic-specific cell states. (3) To develop a patient-derived organoid model of TAP. By collecting adenoma and paired normal colon tissue, we can generate a three-dimensional culture system known as organoids. Using this powerful platform, we can provide deeper resolution of abnormal gene regulation. Moreover, with the development of patient-derived organoids, we aim to establish a tractable model of TAP that is amenable to functional studies (e.g., manipulation of differentiation regulators). This proposal is significant because it addresses a critical gap in our understanding of the long-term consequences of cancer therapy on the gastrointestinal tract. The integration of cutting-edge genomic, epigenomic, and organoid modeling approaches will generate an extensive understanding of TAP and development of precancerous polyposis syndromes without known underlying genetic basis. The anticipated outcomes will not only inform strategies for early detection of TAP but also establish a basis for broader insights into therapy-induced malignancies, potentially improving the clinical care of cancer survivors worldwide.
DFG Programme
WBP Fellowship
International Connection
USA
