Integration of molecular pathological and digital pathological information for a more precise prediction of prognosis in colorectal cancer

结直肠癌是一种异质性疾病，可以根据不同的潜在分子发病机制进行分类。在相同的分子途径上发展的结直肠癌在对治疗的反应和预后方面也可能相似。结直肠癌亚型的研究具有巨大的转化潜力，这些亚型可以通过分子病理学和临床特征相互区分。在DFG后续建议的帮助下，DACHS研究中患者的肿瘤分析将扩展到专门解决精准医学对结直肠癌治疗反应和预后的问题。为此，将在DACHS研究的另外1300例患者中确定主要肿瘤亚型MSI、CIMP、BRAF和KRAS，以便将计划分析的总数增加至3500例。此外，为了将其他有前景和临床相关的生物标志物整合到分析中，将研究其他肿瘤标志物。直到最近，来自肿瘤组织的全基因组甲基化信息已可用于DACHS研究的约1000名患者，其预后意义已被分析和发表。与此同时，具有全基因组甲基化信息的患者数量已增加至>2100。在本项目中，将使用更大的患者人群进行更具体和更有意义的分析。另一个有前途的新肿瘤标志物是免疫评分，这是一种在大型验证研究中建立的预后评分。免疫评分是一种很有前途的预后评分，已在大型验证研究中建立。然而，它在分期和治疗中的作用，以及与其他分子标志物的结合，尚未得到很好的研究，因为这些研究需要大量的患者人群。计划确定2000名患者的免疫评分，可以通过石蜡切片上CD3和CD8基因表达的免疫组织化学染色以及随后的数字病理学评估来确定，这已经在初步工作中成功地进行了测试。由于DACHS研究的大量初步工作，已经建立的肿瘤组织分子表征的分析方法，以及申请人的科学专业知识和相互联系，研究结直肠癌分子亚型的预后和治疗相关关联的先决条件在该后续项目中非常出色。由于患者数量庞大，患者和肿瘤特征广泛，计划的分析具有很高的转化潜力，将为精准医学领域提供新的结果。

Colorectal cancer is a heterogeneous disease that can be classified according to the different underlying molecular pathogenesis. Colorectal carcinomas that have developed over the same molecular pathway are also likely to be similar in their response to therapy and their prognosis. The investigation of subtypes of colorectal cancer, which can be distinguished from each other by molecular pathological and clinical characteristics, holds an enormous translational potential. With the help of the DFG follow-up proposal, the tumor analyses of patients in the DACHS study will be expanded to specifically address questions of precision medicine on the therapeutic response and prognosis in colorectal cancer. For this purpose, the main tumor subtypes MSI, CIMP, BRAF and KRAS will be determined in another 1300 patients of the DACHS study in order to increase the total number to 3500 for the planned analyses. Also, to integrate other promising and clinically relevant biomarkers into the analyses, additional tumor markers will be investigated. Until recently, genome-wide methylation information from tumor tissue has been available for about 1000 patients of the DACHS study, which has been analyzed and published with regard to its prognostic significance. In the meantime, the number of patients with genome-wide methylation information has increased to >2100. Within this project, this much larger patient population will be used to carry out more specific and more meaningful analyses. Another promising new tumor marker is the Immunoscore, a prognostic score that has been established in large validation studies. The Immunoscore is a promising prognostic score that has been established in large validation studies. However, its role in staging and treatment, as well as in combination with other molecular markers, has not yet been well studied, as such studies require large patient populations. It is planned to determine the Immunoscore for 2000 patients, which can be determined by immunohistochemical staining of the gene expression of CD3 and CD8 on paraffin sections with subsequent digital pathological evaluation, which has already been successfully tested in preliminary work.Due to the extensive preliminary work in the DACHS study, the already established analytical methods for the molecular characterization of tumor tissue, as well as the scientific expertise and interconnectedness of the applicants, the prerequisites for the investigations of prognostic and therapy-relevant associations with molecular subtypes of colorectal cancer are excellent in this follow-up project. Due to the large number of patients and the extensive patient and tumor characterization, the planned analyses have a high translational potential and will provide novel results for in the field of precision medicine.