Identification of rare and penetrant germline mutations for gastric cancer

胃癌罕见和渗透性种系突变的鉴定

• 批准号: 433208222
• 负责人: Professor Dr. Peter Krawitz
• 金额: --
• 依托单位: Zentrum für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/433208222?language=en
• 关键词: Identification; rare; penetrant; germline; mutations

As with other common cancers gastric cancer is multifactorial or monogenic in origin. However, the only monogenic form of gastric cancer identified to date is Hereditary Diffuse Gastric Cancer (HDGC), which is caused by highly penetrant mutations in the gene CDH1 (E-cadherin) and restricted to patients with a histopathologically diffuse type of gastric cancer according to the Lauren classification. In recent years, further candidate genes for monogenic forms of gastric cancer have been identified via Whole-Exome Sequencing (WES) approaches. However, in all these studies only CDH1-negative HDGC patients were analyzed and/or the Next Generation Sequencing (NGS) was limited to predefined groups of genes of known oncological relevance.Through work conducted over the past years, the applicants have established the prerequisites for the proposed research and have established the international research network STAR (http://star-project.md/). The aim of STAR is to elucidate the genetic and cell-biological causes of gastric cancer. The STAR Biobank contains biomaterials from > 5,100 European gastric cancer patients, and is an optimal resource for the identification of the entire spectrum of common and rare gene variants and mutations underlying gastric cancer. The applicants now hypothesize that rare, and as yet unidentified, pathogenic gene mutations contribute to gastric cancer in a monogenic manner. The identification of those mutations is of major clinical relevance. Due to their high penetrance, such monogenic forms would have implications for the clinical management of both affected patients and healthy carriers. In order to identify rare and penetrant germline mutations, samples of 300 gastric cancer patients with an extreme early onset (< 45 years) will be subjected to WES. The selection of this cohort was based on a power analysis and the fact, that early age at onset cases are highly enriched among monogenic cancer types. In all patients the presence of CDH1 mutations has been excluded. The WES will be carried out at the West German Genome Center using most modern NGS technology. The applicants will then conduct the bioinformatics work-up using state-of-the-art methods, incl. modern Burden tests in order to prioritize genes and mutations for subsequent analysis. Finally, the applicants will confirm all identified mutations using Sanger sequencing. The generated data will be further analyzed in follow-up projects. The identified cancer genes will be investigated in the entire STAR gastric cancer cohort, which is detailed clinically characterized. These analyses will help to determine the contribution of the identified cancer genes to gastric cancer in detail, and whether this is dependent on the age of disease onset. In addition, first functional studies of new monogenic disease genes will be carried out in order to characterize the respective cellular dysfunction.

与其他常见的癌症一样，胃癌的起源是多因素或单基因。但是，迄今为止确定的唯一单基因胃癌是遗传性弥漫性胃癌（HDGC），它是由基因CDH1（E-钙粘蛋白）高度渗透突变引起的，并且仅限于患有组织病理学上的胃癌类型的患者进行劳伦分类。近年来，通过全外象征测序（WES）方法鉴定出了胃癌单基因形式的进一步候选基因。但是，在所有这些研究中，仅分析CDH1阴性HDGC患者和/或下一代测序（NGS）仅限于已知肿瘤相关性的基因的预定基因组。过去几年进行的工作，申请人已经确定了先决条件。对于拟议的研究，并建立了国际研究网络之星（http://star-project.md/）。明星的目的是阐明胃癌的遗传和细胞生物学原因。 Star Bioband包含来自> 5,100名欧洲胃癌患者的生物材料，并且是鉴定整个普通基因和稀有基因变异和胃癌的突变的最佳资源。现在，申请人假设这种罕见且尚未确定的病原基因突变以单基因方式促进胃癌。这些突变的识别是主要的临床相关性。由于它们的高外观，这种单基因形式将对受影响的患者和健康携带者的临床管理产生影响。为了鉴定罕见和渗透性种系突变，将遭受WES的300例极端发作（<45岁）的胃癌患者的样品。该队列的选择是基于功率分析，事实是，在单基因癌症类型中，发病案例的幼年高度富集。在所有患者中，CDH1突变的存在被排除在外。 WES将使用大多数现代NGS技术在西德基因组中心进行。然后，申请人将使用最先进的方法进行生物信息学检查。现代负担测试是为了确定基因和突变的优先级以进行后续分析。最后，申请人将使用Sanger测序确认所有已识别的突变。生成的数据将在后续项目中进一步分析。确定的癌症基因将在整个Star胃癌队列中进行研究，临床上详细介绍了癌症。这些分析将有助于确定已鉴定的癌症基因对胃癌的贡献，以及这是否取决于疾病发作的时代。此外，将进行新的单基因疾病基因的首次功能研究，以表征各自的细胞功能障碍。