Clonal dynamics and mutational landscape of normal and cancerous tissues in cancer predisposition syndromes

癌症易感综合征中正常组织和癌组织的克隆动态和突变景观

• 批准号: MR/W025353/1
• 负责人: Raheleh Rahbari
• 金额: $ 146.57万
• 依托单位: Wellcome Sanger Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW025353%2F1
• 关键词: Clonal; dynamics; mutational; landscape; normal

Cancer predisposition syndrome, also called inherited cancer predisposition, or familial cancers are usually caused by pathogenic mutation(s) that are inherited from one or both parents and increase the risk of developing cancer at an earlier age compared to the risk for the general population. Although all the cells in the offspring carry the same pathogenic mutation(s), yet only some cell types are sensitive to these changes and transform into malignant tumours. Moreover, some tumours emerge early in these individuals (during childhood), such as sarcoma, while others take longer to form, such as breast cancer (usually it appears around the age of 20 and above). Despite the huge effort in the field to understand tumorigenesis in individuals with cancer predisposition syndromes, yet the cellular processes that cause malignant transformation in some cells but not in every single cell in the body remain unknown. The aim of this study is to:1) Generate a comprehensive mutational landscape across histological normal tissues of individuals with Li-Fraumeni syndrome, which is a type of inherited cancer; 2) Identify factors that cause an early tumour transformation in some cells compared to tumours that emerge later in life;3) Investigate DNA modifications, such as changes in methylation, which may play a role in malignant transformation across different cell types. The results from this study will help us better understand how malignant transformation occurs in some cells in individuals with cancer predisposition syndromes. The outcome will provide important insights into cancer risk and development in general.

癌症易感综合征，又称遗传性癌症易感，或家族性癌症，通常是由父母一方或双方遗传的致病突变(S)引起的，与普通人群的风险相比，这种突变会增加较早患癌症的风险。虽然后代中的所有细胞都带有相同的致病突变(S)，但只有某些细胞类型对这些变化敏感并转化为恶性肿瘤。此外，一些肿瘤在这些人身上出现得很早(在儿童时期)，如肉瘤，而另一些则需要更长的时间才能形成，如乳腺癌(通常出现在20岁及以上)。尽管该领域在了解癌症易感综合征患者的肿瘤发生机制方面做出了巨大努力，但导致某些细胞恶性转化而不是体内每一个细胞恶性转化的细胞过程仍然未知。本研究的目的是：1)生成Li-Fraumeni综合征(一种遗传性癌症)患者组织学正常组织的全面突变图景；2)确定与晚年出现的肿瘤相比，导致某些细胞早期肿瘤转化的因素；3)研究DNA修饰，例如甲基化的变化，这可能在不同类型细胞的恶性转化中起到作用。这项研究的结果将有助于我们更好地了解癌症易感综合征患者的一些细胞如何发生恶性转化。这一结果将为癌症风险和总体发展提供重要的见解。