Periodic Reporting for period 2 - DISCERN (Discovering the causes of three poorly understood cancers in Europe)
Período documentado: 2024-07-01 hasta 2025-12-31
The overall goal of DISCERN is to understand the causes of three poorly understood cancers in Europe; renal, pancreatic and colorectal cancer, and help to explain their geographical distribution, including their high incidence in central and eastern Europe. This will be achieved by combining large-scale European biorepositories comprising population-based cohorts and tumour case-series with state-of-the-art molecular profiling techniques and machine learning approaches. In particular, DISCERN will identify potential new causal risk factors for the three cancers using novel exposomics and proteomics scans, as well detailed geospatial and environmental exposure information from 16 large-scale epidemiological cohorts including almost 900,000 individuals. It will also explore biological mechanisms on how these risk factors are potentially causing these cancer types with a focus on promoting factors in normal tissues using deep sequencing, single cell multi-omics and spatial proteomics. The causal effects of identified cancer risk factors and the cellular signalling responses they trigger will be further evaluated using a panel of stem cells and colon, renal and pancreatic 3D organoids. The results from DISCERN will be disseminated to citizens, patients and policy makers through collaborating patient and participant organizations. DISCERN will provide the critical evidence base required to develop new prevention strategies to tackle the growing burden of renal, pancreatic and colorectal cancer in Europe. This action is part of the Cancer Mission cluster of projects on "Understanding".
During the second reporting period (M19–M36), DISCERN transitioned from preparatory and infrastructural activities to full operational implementation across work packages. The consortium successfully advanced from study design and legal harmonisation to large-scale biosample shipment, generation of multi-omics datasets (metabolomics, microbiome, clonal genomics, proteomics), and implementation of integrative and causal analytical pipelines.
Key achievements during RP2 include:
• Completion of Material and Data Transfer Agreements (MDTAs) with participating cohorts, enabling large-scale shipment of case-cohort plasma samples to IARC (Estonian Biobank DTA finalisation is still pending).
• Centralisation of harmonised covariate and clinical datasets, and implementation of the Secure IT (SIT) platform at IARC, with Data Use Agreements (DUAs) with DISCERN partners in place.
• Establishment of an international cancer case series biorepository within DISCERN framework, expanded to include two additional countries (Spain and Italy), with samples and associated data fully integrated into the analytical pipeline.
• Completion of blood-based biomarker generation in ~3,000 case-series samples, including high-throughput proteomics (~1,500–1,700 proteins) and untargeted mass spectrometry. Similar proteomic profiling of up to 7000 proteins has also been completed in ~5,000 individuals from the EPIC cohort under a case-cohort design.
• Advances in analytical strategies led to the identification of circulating protein signatures associated with survival in the case series and with cancer risk in the EPIC case-cohort, for both renal and colorectal cancers.
• Completion of tissue-based analyses for the renal cancer case series, including spatial proteomics and deep sequencing. Substantial progress has been achieved for the remaining cancer sites. Significant advances have also been made in microbiome profiling of tumour and matched normal tissues, with data generated for approximately half of the targeted cases.
• Deployment of advanced statistical, federated, machine learning, and causal inference pipelines in WP5.
• Validation and application of hiPSC-derived organoid and reporter systems for mechanistic interrogation of suspected carcinogens.
• Continued dissemination activities through European and international patient networks and scientific fora.
Key achievements during RP2 include:
• Completion of Material and Data Transfer Agreements (MDTAs) with participating cohorts, enabling large-scale shipment of case-cohort plasma samples to IARC (Estonian Biobank DTA finalisation is still pending).
• Centralisation of harmonised covariate and clinical datasets, and implementation of the Secure IT (SIT) platform at IARC, with Data Use Agreements (DUAs) with DISCERN partners in place.
• Establishment of an international cancer case series biorepository within DISCERN framework, expanded to include two additional countries (Spain and Italy), with samples and associated data fully integrated into the analytical pipeline.
• Completion of blood-based biomarker generation in ~3,000 case-series samples, including high-throughput proteomics (~1,500–1,700 proteins) and untargeted mass spectrometry. Similar proteomic profiling of up to 7000 proteins has also been completed in ~5,000 individuals from the EPIC cohort under a case-cohort design.
• Advances in analytical strategies led to the identification of circulating protein signatures associated with survival in the case series and with cancer risk in the EPIC case-cohort, for both renal and colorectal cancers.
• Completion of tissue-based analyses for the renal cancer case series, including spatial proteomics and deep sequencing. Substantial progress has been achieved for the remaining cancer sites. Significant advances have also been made in microbiome profiling of tumour and matched normal tissues, with data generated for approximately half of the targeted cases.
• Deployment of advanced statistical, federated, machine learning, and causal inference pipelines in WP5.
• Validation and application of hiPSC-derived organoid and reporter systems for mechanistic interrogation of suspected carcinogens.
• Continued dissemination activities through European and international patient networks and scientific fora.
At 36 months into our 5-year project, it's still early to report outcomes beyond the state of the art. However, foundational work is progressing well, as detailed in the technical report, setting the stage for future advancements.