The IARC Monographs: Updated Procedures for Modern and Transparent Evidence Synthesis in Cancer Hazard Identification.

The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards by independent experts. The Preamble to the IARC Monographs, which outlines these procedures, was updated in 2019, following recommendations of a 2018 expert advisory group. This article presents the key features of the updated Preamble, a major milestone that will enable IARC to take advantage of recent scientific and procedural advances made during the 12 years since the last Preamble amendments. The updated Preamble formalizes important developments already being pioneered in the Monographs program. These developments were taken forward in a clarified and strengthened process for identifying, reviewing, evaluating, and integrating evidence to identify causes of human cancer. The advancements adopted include the strengthening of systematic review methodologies; greater emphasis on mechanistic evidence, based on key characteristics of carcinogens; greater consideration of quality and informativeness in the critical evaluation of epidemiological studies, including their exposure assessment methods; improved harmonization of evaluation criteria for the different evidence streams; and a single-step process of integrating evidence on cancer in humans, cancer in experimental animals, and mechanisms for reaching overall evaluations. In all, the updated Preamble underpins a stronger and more transparent method for the identification of carcinogenic hazards, the essential first step in cancer prevention.

Centralization of the IARC Biobank: Combining Multiple Sample Collections into a Common Platform.

The International Agency for Research on Cancer (IARC) is the World Health Organization's (WHO) cancer research agency. The agency conducts research on cancer with worldwide collaborations, adopting a multidisciplinary approach of epidemiology and laboratory-based studies on cancer causes, as well as preventive interventions. The IARC Biobank stores multiple collections of samples and conducts preanalytical services for studies conducted worldwide in support of the research activities. Traditionally, the multiple collections from these studies were managed by the individual research groups in different project-specific databases. In 2010, a program to centralize sample collections into a single platform was initiated by adopting a common database with the introduction of a minimum dataset for sample collections received at IARC. The process involved checking data files, verifying the storage location of samples, conducting data harmonization, and importing or migrating existing data from project-specific spreadsheets and databases into the common database. In addition to the creation of a common biobank database and an up-to-date inventory of IARC's biological resources, a governance structure was established. The creation of the Biobank Steering Committee and the adoption of an access policy is to facilitate and guide the sharing of IARC's resources in a transparent manner, while taking into account Ethical, Legal, and Social Issues.

Cancer Prevention Europe.

The case for cancer prevention in Europe is the same as for all other parts of the world. The number of cancers is increasing, driven by demographic change and evolution in the exposure to risk factors, while the cost of treating patients is likewise spiralling. Estimations suggest that around 40% of cancers in Europe could be prevented if current understanding of risk and protective factors was translated into effective primary prevention, with further reductions in cancer incidence and mortality by screening, other approaches to early detection, and potentially medical prevention. However, the infrastructure for cancer prevention tends to be fragmented between and within different countries in Europe. This lack of a coordinated approach recently led to the foundation of Cancer Prevention Europe (Forman et al., 2018), a collaborative network with the main aims of strengthening cancer prevention in Europe by increasing awareness of the needs, the associated required resources and reducing inequalities in access to cancer prevention across Europe. This article showcases the need for strengthening cancer prevention and introduces the objectives of Cancer Prevention Europe and its foreseen future role in reducing the European cancer burden.

Trends of serum phospholipid fatty acids over time in rural Uganda: evidence of nutritional transition?

Non-communicable diseases are projected to become the most common causes of death in Africa by 2030. The impact on health of epidemiological and nutritional transitions in sub-Saharan Africa remains unclear. To assess the trends of dietary fatty acids over time in Uganda, we examined fatty acids in serum collected from individuals in rural south-west Uganda, at three time points over two decades. Independent cross-sectional samples of 915 adults and children were selected from the general population cohort in 1990 (n 281), 2000 (n 283) and 2008 (n 351). Serum phospholipid fatty acids were measured by GC. Multivariate regression analyses were performed to compare the geometric means of fatty acids by time period. Serum fatty acid profiling showed high proportions of SFA, cis-MUFA and industrial trans-fatty acids (iTFA), likely to be biomarkers of high consumption of palm oil and hydrogenated fats. In contrast, proportions of n-6 and n-3 PUFA from vegetable oils and fish were low. From 1990 to 2008, serum phospholipids showed increases in absolute amounts of SFA (17·3 % increase in adults and 26·4 % in children), MUFA (16·7 % increase in adults and 16·8 % in children) and n-6:n-3 PUFA (40·1 % increase in adults and 39·8 % in children). The amount of elaidic acid, iTFA from hydrogenated fats, increased in children (60·1 % increase). In this rural Ugandan population, we show evidence of unfavourable trends over time of dietary fatty acids.

Primary prevention: a need for concerted action.

The burden of cancer is increasing worldwide, and Europe is no exception in this regard. Cancer incidence rate for men in 2018, excluding nonmelanoma skin cancers, averaged over the 40 UN-defined European countries has been estimated as 436/100 000. For women, the estimated incidence rate is 332.6/100 000. Although mortality rates are declining in most European countries, the total number of cancer deaths continues to rise due to an increase in the number of older people in the age range when the cancer typically occurs. The increase in incident cases and cancer deaths increases the pressure on healthcare infrastructure and related costs, thus presenting a challenge to health service sustainability in countries. In the general population, there remains a perception of an ever-increasing cancer risk. Hence, treatment alone is not a solution to address the cancer burden. At the same time, recent estimates of preventable fractions of cancer suggest that about half of all cancer cases could be prevented through rigorous implementation of successful prevention measures, among other actions, by following the cancer prevention recommendations of the European Code against Cancer. Smoking alone explains almost half of all preventable cancers, and the scattered way of implementing tobacco control in Europe with still increasing numbers of lung cancers in women demonstrates the gap between prevention potential and effectively implemented prevention. Cancer prevention clearly needs more resources, stronger support from decision-makers and society, and a solid network to better speak with one voice. The newly established 'Cancer Prevention Europe' (Forman et al., ) offers promising opportunities for the latter.

Impaired growth in rural Gambian infants exposed to aflatoxin: a prospective cohort study.

BACKGROUND: Exposure to aflatoxin, a mycotoxin produced by fungi that commonly contaminates cereal crops across sub-Saharan Africa, has been associated with impaired child growth. We investigated the impact of aflatoxin exposure on the growth of Gambian infants from birth to two years of age, and the impact on insulin-like growth factor (IGF)-axis proteins. METHODS: A subsample (N = 374) of infants from the Early Nutrition and Immune Development (ENID) trial (ISRCTN49285450) were included in this study. Aflatoxin-albumin adducts (AF-alb) were measured in blood collected from infants at 6, 12 and 18 months of age. IGF-1 and IGFBP-3 were measured in blood collected at 12 and 18 months. Anthropometric measurements taken at 6, 12, 18 and 24 months of age were converted to z-scores against the WHO reference. The relationship between aflatoxin exposure and growth was analysed using multi-level modelling. RESULTS: Inverse relationships were observed between lnAF-alb and length-for-age (LAZ), weight-for-age (WAZ), and weight-for-length (WLZ) z-scores from 6 to 18 months of age (ß = - 0·04, P = 0·015; ß = - 0·05, P = 0.003; ß = - 0·06, P = 0·007; respectively). There was an inverse relationship between lnAF-alb at 6 months and change in WLZ between 6 and 12 months (ß = - 0·01; P = 0·013). LnAF-alb at 12 months was associated with changes in LAZ and infant length between 12 and 18 months of age (ß = - 0·01, P = 0·003; ß = - 0·003, P = 0·02; respectively). LnAF-alb at 6 months was associated with IGFBP-3 at 12 months (r = - 0·12; P = 0·043). CONCLUSIONS: This study found a small but significant effect of aflatoxin exposure on the growth of Gambian infants. This relationship is not apparently explained by aflatoxin induced changes in the IGF-axis.

Toward the World Code Against Cancer.

Overwhelmed by an abundance of often confusing, ambiguous, or apparently contradictory messages on disease prevention in today's multiple media streams, the general public would surely value authoritative, clear, and evidence-based instructions on how to actively contribute to the reduction of their cancer risk. The European Code Against Cancer is a set of 12 recommendations for individuals on how to reduce cancer risk. The Code carries the authority and reliability of expert scientists working under the coordination of the International Agency for Research on Cancer, the cancer research agency of the WHO. The Code's messages are aimed at individuals and have been enthusiastically promoted by European cancer associations. The experience of developing and promoting the European Code has generated interest in developing analogous recommendations for other regions of the world. Under the overall umbrella of a World Code Against Cancer using the same International Agency for Research on Cancer methodology, regional Codes could be developed, focused on regions sufficiently large and distinct to merit development of versions adapted to regional differences in risk factors and cancer patterns. Consideration of such an adapted model illustrates why a simple translation of the European Code would not be sufficient to promote cancer prevention globally.

Tackling cancer burden in low-income and middle-income countries: Morocco as an exemplar.

Examples of successful implementations of national cancer control plans in low-income or middle-income countries remain rare. Morocco, a country where cancer is already the second leading cause of death after cardiovascular diseases, is one exception in this regard. Population ageing and lifestyle changes are the major drivers that are further increasing the cancer burden in the country. Facing this challenge, the Moroccan Ministry of Health has developed a we l planned and pragmatic National Plan for Cancer Prevention and Control (NPCPC) that, since 2010, has been implemented with government financial support to provide basic cancer care services across the entire range of cancer control. Several features of the development and implementation of the NPCPC and health-care financing in Morocco provide exemplars for other low-income and middle-income countries to follow. Additionally, from the first 5 years of NPCPC, several areas were shown to require further focus through implementation research, notably in strengthening cancer awareness, risk reduction, and the referral pathways for prevention, early detection, treatment, and follow-up care. Working together with a wide range of stakeholders, and engagement with stakeholders outside the health-care system on a more holistic approach can provide further opportunities for the national authorities to build on their successes and realise the full potential of present and future cancer control efforts in Morocco.

Roadmap for investigating epigenome deregulation and environmental origins of cancer.

The interaction between the (epi)genetic makeup of an individual and his/her environmental exposure record (exposome) is accepted as a determinant factor for a significant proportion of human malignancies. Recent evidence has highlighted the key role of epigenetic mechanisms in mediating gene-environment interactions and translating exposures into tumorigenesis. There is also growing evidence that epigenetic changes may be risk factor-specific ("fingerprints") that should prove instrumental in the discovery of new biomarkers in cancer. Here, we review the state of the science of epigenetics associated with environmental stimuli and cancer risk, highlighting key developments in the field. Critical knowledge gaps and research needs are discussed and advances in epigenomics that may help in understanding the functional relevance of epigenetic alterations. Key elements required for causality inferences linking epigenetic changes to exposure and cancer are discussed and how these alterations can be incorporated in carcinogen evaluation and in understanding mechanisms underlying epigenome deregulation by the environment.

Viral driven epigenetic events alter the expression of cancer-related genes in Epstein-Barr-virus naturally infected Burkitt lymphoma cell lines.

Epstein-Barr virus (EBV) was identified as the first human virus to be associated with a human malignancy, Burkitt's lymphoma (BL), a pediatric cancer endemic in sub-Saharan Africa. The exact mechanism of how EBV contributes to the process of lymphomagenesis is not fully understood. Recent studies have highlighted a genetic difference between endemic (EBV+) and sporadic (EBV-) BL, with the endemic variant showing a lower somatic mutation load, which suggests the involvement of an alternative virally-driven process of transformation in the pathogenesis of endemic BL. We tested the hypothesis that a global change in DNA methylation may be induced by infection with EBV, possibly thereby accounting for the lower mutation load observed in endemic BL. Our comparative analysis of the methylation profiles of a panel of BL derived cell lines, naturally infected or not with EBV, revealed that the presence of the virus is associated with a specific pattern of DNA methylation resulting in altered expression of cellular genes with a known or potential role in lymphomagenesis. These included ID3, a gene often found to be mutated in sporadic BL. In summary this study provides evidence that EBV may contribute to the pathogenesis of BL through an epigenetic mechanism.

Cancer prevention as part of precision medicine: 'plenty to be done'.

Cancer burden worldwide is projected to rise from 14 million new cases in 2012 to 24 million in 2035. Although the greatest increases will be in developing countries, where cancer services are already hard pressed, even the richest nations will struggle to meet demands of increasing patient numbers and spiralling treatment costs. No country can treat its way out of the cancer problem. Consequently, cancer control must combine improvements in treatment with greater emphasis on prevention and early detection. Cancer prevention is founded on describing the burden of cancer, identifying the causes and evaluating and implementing preventive interventions. Around 40-50% of cancers could be prevented if current knowledge about risk factors was translated into effective public health strategies. The benefits of prevention are attested to by major successes, for example, in tobacco control, vaccination against oncogenic viruses, reduced exposure to environmental and occupational carcinogens, and screening. Progress is still needed in areas such as weight control and physical activity. Fresh impetus for prevention and early detection will come through interdisciplinary approaches, encompassing knowledge and tools from advances in cancer biology. Examples include mutation profiles giving clues about aetiology and biomarkers for early detection, to stratify individuals for screening or for prognosis. However, cancer prevention requires a broad perspective stretching from the submicroscopic to the macropolitical, recognizing the importance of molecular profiling and multisectoral engagement across urban planning, transport, environment, agriculture, economics, etc., and applying interventions that may just as easily rely on a legislative measure as on a molecule.

Genomics of Cancer and a New Era for Cancer Prevention.

A primary justification for dedicating substantial amounts of research funding to large-scale cancer genomics projects of both somatic and germline DNA is that the biological insights will lead to new treatment targets and strategies for cancer therapy. While it is too early to judge the success of these projects in terms of clinical breakthroughs, an alternative rationale is that new genomics techniques can be used to reduce the overall burden of cancer by prevention of new cases occurring and also by detecting them earlier. In particular, it is now becoming apparent that studying the genomic profile of tumors can help to identify new carcinogens and may subsequently result in implementing strategies that limit exposure. In parallel, it may be feasible to utilize genomic biomarkers to identify cancers at an earlier and more treatable stage using screening or other early detection approaches based on prediagnostic biospecimens. While the potential for these techniques is large, their successful outcome will depend on international collaboration and planning similar to that of recent sequencing initiatives.

The mycotoxin aflatoxin B1 stimulates Epstein-Barr virus-induced B-cell transformation in in vitro and in vivo experimental models.

Although Epstein-Barr virus (EBV) infection is widely distributed, certain EBV-driven malignancies are geographically restricted. EBV-associated Burkitt's lymphoma (eBL) is endemic in children living in sub-Saharan Africa. This population is heavily exposed to food contaminated with the mycotoxin aflatoxin B1 (AFB1). Here, we show that exposure to AFB1 in in vitro and in vivo models induces activation of the EBV lytic cycle and increases EBV load, two events that are associated with an increased risk of eBL in vivo. AFB1 treatment leads to the alteration of cellular gene expression, with consequent activations of signaling pathways, e.g. PI3K, that in turn mediate reactivation of the EBV life cycle. Finally, we show that AFB1 triggers EBV-driven cellular transformation both in primary human B cells and in a humanized animal model. In summary, our data provide evidence for a role of AFB1 as a cofactor in EBV-mediated carcinogenesis.