The Section of Mechanisms of Carcinogenesis (MCA), headed by Dr Zdenko Herceg, is responsible for studies aimed at elucidating molecular mechanisms by which environmental exposures induce genetic and epigenetic alterations and deregulate molecular pathways critical for cancer development and progression. Increasingly, evaluation of the carcinogenic risks posed to humans by environmental exposures will draw upon mechanistic data. In this context, MCA is well placed to enhance the evidence base for understanding the causes and prevention of cancer.
The Section comprises two Groups: the Molecular Mechanisms and Biomarkers Group (MMB) and the Epigenetics Group (EGE), which work in close collaboration to create synergies and better exploit and further expand unique research tools and expertise. Recent developments in the Section brought about by new strategic decisions and recruitments have enabled a shift in approach, with a greater emphasis on integrated omics-level strategies and methods for studying mechanisms of carcinogenesis and biomarker discovery. The added expertise brought about by the recruitments has enabled the development of new, multidisciplinary projects that exploit recent conceptual and technological advances. These recruitments were essential for the overall strategy of MCA and the development of new cross-cutting research themes in the area of mechanisms of carcinogenesis carried out jointly by EGE, MMB, and other research groups at IARC.
Future directions and strategic vision
Improving the knowledge of mechanisms of carcinogenesis related to environmental exposures provides a foundation for studies of cancer etiology, carcinogen evaluation, and cancer prevention, the core activities of IARC. The main objective of the Section is to provide the evidence base for the study of cancer causation and prevention by elucidating the molecular mechanisms by which genetic and epigenetic alterations resulting from environmental exposures alter critical molecular pathways and promote cancer development. Major emphasis is placed on discerning events that precede or drive tumour initiation and progression related to environmental exposures.
An important part of MCA′s strategy is to conduct research to develop genomic and epigenomic methodologies, profiling strategies, and bioinformatics tools and resources that are applicable to biobanks associated with population-based studies. MCA also contributes to the development of translational studies, through the discovery of mechanism-based biomarkers of exposure and cancer risk, and to cancer research that is relevant, although not exclusive, to low- and middle-income countries (LMICs). This strategic vision is consistent with the IARC Medium-Term Strategy (MTS) for 2010—2015 (approved by the 52nd Session of the Governing Council in 2010) and with the MTS for 2016—2020, which is currently being prepared, where elucidating the mechanisms of carcinogenesis related to environmental and lifestyle exposures is one of the core activities of the Agency.
New and original research topics developed by MCA take advantage of state-of-the-art, powerful molecular/cell biology and functional genomics tools, recent progress in understanding of the cancer (epi)genome, and development of genomic databases and new bioinformatics tools. The application of “omics” approaches brought about by the advent of less costly profiling technologies and access to large population-based studies make it possible to identify new biomarkers and test the “exposome” concept, a new initiative aiming to describe the breadth of carcinogenic exposure throughout an individual′s lifetime. To this end, MCA′s extensive expertise in the development of methodological approaches and cost-effective tools for high-throughput (epi)genomic profiling is central in enabling IARC to apply genome-wide assessments to epidemiological studies.
These developments open up an exciting opportunity to identify and characterize the key molecular pathways underpinning carcinogenesis, which are expected to elucidate some important aspects of cancer etiology and reveal prevention opportunities.
With the opportunities provided by these advances in mind, MCA′s strategy will focus on two priority areas. First, MCA studies are aimed at providing critical insights into mechanisms of carcinogenesis through the identification of molecular alterations and molecular pathways deregulated by specific cancer risk factors. This will be achieved through mechanistic studies of functionally important (epi)genetic “driver” events and molecular pathways altered by specific cancer risk agents (with a focus on a set of genotoxic and non-genotoxic agents prioritized according to their relevance to cancer etiology and prevention), using in vitro models and state-of-the-art approaches including (epi)genome-wide screens and functional genomics. The identification and functional characterization of “driver” events and molecular pathways deregulated by specific risk factors are expected to advance our knowledge of mechanisms of carcinogenesis relevant to the causes and prevention of cancer.
Second, MCA is involved in identifying molecular biomarkers of exposure and cancer risk and contributing to the characterization of key components of the exposome. MCA uses cutting-edge (epi)genomics, population-based cohorts, and innovative bioinformatics tools to investigate (epi)genomic profiles of specific cancers and surrogate tissues and to identify signatures of cancer risk and exposures. The primary focus will be on cancers of the breast, urinary tract, and liver. MCA participates in an interdisciplinary approach aimed at characterizing exposures throughout the life-course (with a particular focus on the fetal exposome and childhood cancer) by building upon advances in laboratory science (“omics” technologies) and unique samples from international population-based cohorts (collaboration with IARC Groups: Genetic Cancer Susceptibility (GCS), Biomarkers (BMA), Infections and Cancer Biology (ICB), and Biostatistics (BST)). Identification of epigenetic signatures linked to measures of environmental exposures throughout life (the exposome) should facilitate the development of (epi)genome-based biomarkers of cancer risk and mechanism-based biomarkers of exposures. Finally, MCA will build upon whole-(epi)genome profiles released by major sequencing efforts (TCGA, IHEC) and take advantage of existing molecular epidemiology studies in LMICs and targeted (epi)genomics to develop an approach for (epi)genomic classification in order to distinguish screen-detected or early-stage lesions according to their risk of progression to an invasive process (the focus will be on breast cancer; collaboration with IARC Groups and Sections: MMB, GCS, Molecular Pathology (MPA), and Nutritional Epidemiology (NEP)).
Demands for faster, more affordable, and less labour-intensive strategies are increasingly met by several emerging technologies that have demonstrated the capacity to deliver next-generation solutions for fast and cost-effective (epi)genome sequencing. Therefore, the development of epigenomic and profiling strategies, as well as bioinformatics tools, applicable to population-based cohorts, epidemiology, and carcinogen evaluation remains an essential part of MCA′s strategy. Furthermore, MCA develops pipelines for (epi)genome-wide profiling and targeted (epi)genetics in high-throughput settings and robust bioinformatics analysis, all of which should facilitate identification of causal pathways linking the exposome measures and early mechanistic effects leading to cancer. The development of new in vitro assays should facilitate the incorporation of (epi)genetic and mechanistic data into carcinogen evaluation by the Section of IARC Monographs (IMO). Recent investments in bioinformatics personnel in MCA and GCS should provide centralized, continuous support for analysis of the next level of complex and cross-omics profiling data, the results of which constitute a strong basis for formulating and testing mechanistic hypotheses on cancer etiology and prevention. This will, in turn, enhance collaborations across Groups/Sections and leverage international collaborations (including those from LMICs).
The Section receives funding from the European Union, the National Institute of Health –National 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; Bill & Melinda Gates Foundation; Ligue Nationale Contre le Cancer, France; and Swiss Bridge).