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Section of Mechanisms of Carcinogenesis

The Section of Mechanisms of Carcinogenesis (MCA), headed by Dr Zdenko Herceg, conducts mechanistic (hypothesis-driven) studies as well as studies aimed at advancing the understanding of cancer causation and promoting international collaboration, the core activities of IARC. MCA’s studies are interdisciplinary in nature, and the synergistic collaborations with other IARC laboratory-based scientists and epidemiologists as well as international collaboration groups advance major MCA programmes.

The Section comprises two groups: the Epigenetics Group (EGE) and the Molecular Mechanisms and Biomarkers Group (MMB), whose corresponding research programmes are complementary with respect to methodological approaches and in their shared ultimate objective of identifying causal links between environmental factors and cancer and identifying and validating cancer biomarkers.

EGE combines molecular epidemiology and experimental studies aimed at investigating the role of epigenetic changes and deregulated pathways induced by environmental or lifestyle factors in cancer development and identifying cancer biomarkers. EGE also develops epigenomic methodologies, profiling strategies, and bioinformatics tools, applicable to population-based cohorts and molecular epidemiology studies coordinated by IARC researchers and external collaborators.
More detailed description of EGE.

MMB is responsible for studies aimed at investigating the effects of environmental exposures on genetic changes (mutations) and their link to carcinogenesis. MMB builds on new and existing collaborative work and combines experimental (mechanistic) studies with molecular epidemiology studies on human biospecimens using genomic platforms, molecular and cell biology, and biochemistry tools.
More detailed description of MMB.

Future directions and strategic vision

Identifying the causal pathways linking environmental or lifestyle exposures to tumorigenesis and gaining insights into molecular mechanisms underlying the associations observed in epidemiological studies (biological plausibility) provide a foundation for studies of cancer etiology, carcinogen evaluation, and cancer prevention. The overarching objective of MCA is to advance the understanding of cancer causes by investigating genetic and epigenetic patterns and interrelated molecular pathways deregulated by exposure risk factors and the underlying mechanisms of carcinogenesis, thus enhancing the evidence base for cancer prevention. This is achieved by exploiting conceptual and technological advances in molecular and cell biology (e.g. CRISPR/Cas9 and organoids), genetics (with a focus on mutation signatures and DNA damage signalling as opposed to genome-wide association studies or analysis of single-nucleotide polymorphisms), and epigenetics (with a focus on DNA methylation and chromatin modulations). MCA’s work capitalizes on the availability of unique population-based cohorts and case–control and intervention studies as well as the Section’s capacity and expertise in integrating wet- and dry-laboratory-based research within IARC’s unique international research setting.

The key elements of MCA’s strategy are developing innovative research and implementing (epi)genomic and profiling methodologies and bioinformatics and biostatistics tools applicable to experimental models and biobanks associated with population-based and case–control studies. The Section’s ambition is also to place more emphasis on potential contributions to translational studies, through the discovery of mechanism-based biomarkers of exposure and risk stratification. MCA applies state-of-the-art molecular and cell biology and functional genomics tools, building on the latest knowledge of the cancer (epi)genome, genomic databases, and new bioinformatics tools. Given that the demand for affordable and less labour-intensive strategies is increasingly met by several emerging technologies that enable robust and cost-effective (epi)genome analysis, the adoption of (epi)genomic and profiling methodologies and bioinformatics tools applicable to large series of human tumour and normal tissue samples as well as experimental models remains an essential part of the MCA strategy. MCA is increasingly involved in the development of translational studies (such as those involving several interventions aimed at reducing cancer risk or cancer recurrence) and in cancer research that is relevant to, although not exclusive to, low- and middle-income countries. This strategic vision is fully aligned with the IARC Medium-Term Strategy for 2016–2020 and with the Medium-Term Strategy for 2021–2025, which is currently being prepared.

Considering these objectives and opportunities, MCA has an important role to play in IARC’s overall mission by extending the current knowledge of cancer etiology and by providing the evidence base for carcinogen evaluation and cancer prevention. For the next 5 years, MCA’s strategy will build on its strengths and recent achievements and capitalize on opportunities brought about by conceptual and technological advances in the fields of laboratory science, molecular epidemiology, and in silico and computational science. The Section will focus on three priority areas: (i) environmental exposures, (epi)genetic changes, and cancer risk throughout the life-course, (ii) the functional role of genetic and epigenetic changes in carcinogenesis, and (iii) obesity, epigenetic changes, and cancer.

The Section’s ambition is to remain at the forefront of the field of laboratory science and molecular epidemiology by adopting new conceptual and technological advances and by capitalizing on IARC’s unique role in international cancer research. Specifically, MCA will reinforce and further expand its expertise and wet- and dry-laboratory components across three major disciplines: molecular epidemiology, molecular biology, and bioinformatics and biostatistics. This will include (i) enhancing the wet-lab pipelines for next-generation sequencing-based (epi)genome analysis (with a focus on medium-scale versatile platforms that enable a rapid and cost-effective replication/validation of the hits identified by large-scale genome-wide sequencing (which is typically done through outsourcing), (ii) the application of genome-wide functional screens in human cultured cells and organoids in combination with genome-editing tools, (iii) the development of rapid models for mutational signature analysis through single-cell sequencing of the genome and transcriptome, and (iv) the development and advancement of bioinformatics and biostatistics tools with application to molecular biology and molecular epidemiology.

The Section receives funding from the European Union, the National Institute of HealthNational Cancer Institute (USA), the Institut National du Cancer (INCa, France), and international and national cancer charities: Association pour la Recherche sur le Cancer (ARC, France), Canadian Institutes of Health Research (CIHR, Canada), INSERM (France), World Cancer Research Fund (United Kingdom), Bill & Melinda Gates Foundation (USA), and Ligue Nationale Contre le Cancer (France).

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