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

评估肾移植后恶性肿瘤的遗传风险 - 一项试点研究（KTx-Cancer）

• 批准号: 471294925
• 负责人: Professor Dr. Jan Halbritter
• 金额: --
• 依托单位: Institut für Genetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/471294925?language=en
• 关键词: Assessing; genetic; risk; post; kidney

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.

与一般人群相比，肾移植（KTx）后恶性肿瘤的发生率显著增加，癌症是肾移植受者死亡的主要原因之一。移植后恶性肿瘤（PTM）最常发生为非黑色素瘤皮肤癌（NMSC），其次是其他癌症实体，如肾细胞癌（RCC）。PTM被认为是内在遗传易感性和外在因素（如日晒、免疫抑制和致癌病毒感染）共同作用的结果；所有这些都损害了内在的抗癌防御。虽然外界因素已被广泛研究，但对ktx受体PTM的个体遗传基础知之甚少。在这个项目提案中，我们试图回顾性地确定在我们机构接受肾移植的患者的生殖系和体细胞易感性的遗传因素（n=400）。具体而言，我们提出以下三个具体目标：i)首先，我们将确定100例PTM患者中单基因癌症综合征的患病率和罕见致病变异的总负担。ii)其次，我们的目标是通过我们队列中的多基因风险评分（PRS）计算来研究已知常见风险变异对NMSC和RCC的遗传易感性。iii)第三，我们将评估我们的ptm病例中NMSC和RCC的确定肿瘤组织的体细胞突变和表观遗传特征，并将其与普通人群中已知的癌症模式进行比较。通过这个项目，我们将生成关于如何根据ktx接受者患PTM的风险对其进行分层的新数据。获得的见解可能会导致未来引入风险调整免疫抑制剂制度，并为及时启动ktx受体亚组癌症预防措施的前瞻性研究奠定基础。