Assessing genetic risk of post-kidney transplantation malignancy - a pilot study (KTx-Cancer)

• Applicant: Professor Dr. Jan Halbritter
• Subject Area: Nephrology ; Human Genetics
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 471294925

Incidence of malignancy is significantly increased after kidney transplantation (KTx) compared to the general population and cancer is one of the leading causes of death among KTx-recipients. Post-transplant malignancy (PTM) most often occurs as non-melanoma skin cancer (NMSC) followed by other cancer entities, such as renal cell carcinoma (RCC). PTM is thought to develop as a consequence of intrinsic genetic predisposition and extrinsic factors, such as sun exposure, immunosuppression, and oncogenic virus infection; all of which compromises endogenous anti-cancer defense. While extrinsic factors have been widely investigated, little is known on the individual genetic basis of PTM in KTx-recipients. With this project proposal, we seek to retrospectively determine genetic factors of germline and somatic susceptibility in patients who received a kidney transplant in our institution (n=400). In detail, we propose the following three specific aims: i) first, we will determine the prevalence of monogenic cancer syndromes and the aggregate burden of rare pathogenic variants in 100 patients with PTM. ii) second, we aim to investigate genetic susceptibility of NMSC and RCC conferred by known common risk variants through polygenic risk score (PRS) calculation in our cohort. iii) third, we will assess ascertained tumor tissues of NMSC and RCC in our PTM-cases for their somatic mutations and epigenetic signatures in comparison to known cancer patterns in the general population. With this project, we will generate novel data on how to stratify KTx-recipients with regards to their hazard of developing PTM. Gained insights may lead to future introduction of risk-adjusted immunosuppressant regimes and build the basis for prospective studies on timely initiation of cancer prevention measures in subgroups of KTx-recipients.

• DFG Programme: Research Grants
• Co-Investigators: Dr. Johannes Münch; Dr. Bernt Popp; Dr. Antje Richter