Role of aneuploidy in the carcinogenic process: Part 3 of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases
Role of aneuploidy in the carcinogenic process: Part 3 of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases
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- dc.contributor.author
- Tweats, David
- Eastmond, David
- Lynch, Anthony M.
- Elhajouji, Azeddine
- Froetschl, Roland
- Kirsch-Volders, Micheline
- Marchetti, Francesco
- Masumura, Kenichi
- Pacchierotti, Francesca
- Schuler, Maik
- dc.date.accessioned
- 2024-03-22T19:45:53Z
- dc.date.available
- 2024-03-22T19:45:53Z
- dc.date.issued
- 2019-03-29
- dc.description - en
- Health Canada supports the development, validation and improvement of test guidelines for the Organisation for the Economic Co-operation and Development (OECD). These guidelines are routinely used for assessing chemicals for mutagenicity (changes in the sequence of the DNA) or clastogenicity (induction of breaks in the DNA). However, guidelines are not yet available to properly assess the ability of chemicals to induce changes in chromosome number, a condition called aneuploidy and that is associated with cancer development and hereditary diseases such as Down syndrome. To address this gap, a group of international experts from various governments, industry and academia met in Tokyo, Japan in November 2017 as part of the International Workshops on Genotoxicity Testing, to discuss the role of aneugens (chemicals that induce aneuploidy) in human health risk assessment. The work from the group is summarized in three companion papers. In this third paper, the group conducted a review of the scientific literature to reach a consensus on the role of chemically induced aneuploidy in cancer development and progression (carcinogenesis). The group agreed that the scientific evidence suggests that is it unlikely that the induction of aneuploidy plays a primary role in cancer development. The available data show that all chemicals that induce aneuploidy and that have been shown to induce cancer in humans and/or laboratory animals have other carcinogenic characteristics, such as mutagenicity and clastogenicity, that are more likely to play a role in the carcinogenic process. Moreover, those aneugens that do not possess these additional characteristics, do not induce cancer in laboratory animals. The comprehensive review presented in this paper should help regulators to identify and risk manage aneugens.
- dc.description.abstract - en
- Aneuploidy is regarded as a hallmark of cancer, however, its role is complex with both pro- and anti-carcinogenic effects evident. In this IWGT review, we consider the role of aneuploidy in cancer biology; cancer risk associated with constitutive aneuploidy; rodent carcinogenesis with known chemical aneugens; and chemotherapy-related malignant neoplasms. Aneuploidy is seen at various stages in carcinogenesis. However, the relationship between induced aneuploidy occurring after exposure and clonal aneuploidy present in tumours is not clear. Recent evidence indicates that the induction of chromosomal instability (CIN), may be more important than aneuploidy per se, in the carcinogenic process. Down Syndrome, trisomy 21, is associated with altered hematopoiesis in utero which, in combination with subsequent mutations, results in an increased risk for acute megakaryoblastic and lymphoblastic leukemias. In contrast, there is reduced cancer risk for most solid tumours in Down Syndrome. Mouse models with high levels of aneuploidy are also associated with increased cancer risk for particular tumours with long latencies, but paradoxically other types of tumour often show decreased incidence. The aneugens reviewed that induce cancer in humans and animals all possess other carcinogenic properties, such as mutagenicity, clastogenicity, cytotoxicity, organ toxicities, hormonal and epigenetic changes which likely account for, or interact with aneuploidy, to cause carcinogenesis. Although the role that aneuploidy plays in carcinogenesis has not been fully established, in many cases, it may not play a primary causative role. Tubulin-disrupting aneugens that do not possess other properties linked to carcinogenesis, were not carcinogenic in rodents. Similarly, in humans, for the tubulin-disrupting aneugens colchicine and albendazole, there is no reported association with increased cancer risk. There is a need for further mechanistic studies on agents that induce aneuploidy, particularly by mechanisms other than tubulin disruption and to determine the role of aneuploidy in pre-neoplastic events and in early and late stage neoplasia.
- dc.description.abstract-fosrctranslation - fr
- Aneuploidy is regarded as a hallmark of cancer, however, its role is complex with both pro- and anti-carcinogenic effects evident. In this IWGT review, we consider the role of aneuploidy in cancer biology; cancer risk associated with constitutive aneuploidy; rodent carcinogenesis with known chemical aneugens; and chemotherapy-related malignant neoplasms. Aneuploidy is seen at various stages in carcinogenesis. However, the relationship between induced aneuploidy occurring after exposure and clonal aneuploidy present in tumours is not clear. Recent evidence indicates that the induction of chromosomal instability (CIN), may be more important than aneuploidy per se, in the carcinogenic process. Down Syndrome, trisomy 21, is associated with altered hematopoiesis in utero which, in combination with subsequent mutations, results in an increased risk for acute megakaryoblastic and lymphoblastic leukemias. In contrast, there is reduced cancer risk for most solid tumours in Down Syndrome. Mouse models with high levels of aneuploidy are also associated with increased cancer risk for particular tumours with long latencies, but paradoxically other types of tumour often show decreased incidence. The aneugens reviewed that induce cancer in humans and animals all possess other carcinogenic properties, such as mutagenicity, clastogenicity, cytotoxicity, organ toxicities, hormonal and epigenetic changes which likely account for, or interact with aneuploidy, to cause carcinogenesis. Although the role that aneuploidy plays in carcinogenesis has not been fully established, in many cases, it may not play a primary causative role. Tubulin-disrupting aneugens that do not possess other properties linked to carcinogenesis, were not carcinogenic in rodents. Similarly, in humans, for the tubulin-disrupting aneugens colchicine and albendazole, there is no reported association with increased cancer risk. There is a need for further mechanistic studies on agents that induce aneuploidy, particularly by mechanisms other than tubulin disruption and to determine the role of aneuploidy in pre-neoplastic events and in early and late stage neoplasia.
- dc.description.fosrctranslation - fr
- Santé Canada soutient l'élaboration, la validation et l'amélioration des lignes directrices en matière d'essais pour l'Organisation de coopération et de développement économiques (OCDE). Ces lignes directrices sont couramment utilisées pour évaluer les produits chimiques en termes de mutagénicité (modifications dans la séquence de l'ADN) ou de clastogénicité (induction de cassures dans l'ADN). Cependant, il n’existe pas encore de lignes directrices permettant d’évaluer correctement la capacité des produits chimiques à induire des modifications du nombre de chromosomes, une condition appelée aneuploïdie et associée au développement du cancer et à des maladies héréditaires telles que le syndrome de Down. Pour combler cette lacune, un groupe d'experts internationaux provenant de divers gouvernements, de l'industrie et du monde universitaire s'est réuni à Tokyo, au Japon, en novembre 2017, dans le cadre des ateliers internationaux sur les tests de génotoxicité, pour discuter du rôle des aneugènes (produits chimiques qui induisent l'aneuploïdie) dans la santé humaine. l'évaluation des risques. Le travail du groupe est résumé dans trois articles complémentaires. Dans ce troisième article, le groupe a procédé à une revue de la littérature scientifique pour parvenir à un consensus sur le rôle de l'aneuploïdie induite chimiquement dans le développement et la progression du cancer (carcinogenèse). Le groupe a convenu que les preuves scientifiques suggèrent qu'il est peu probable que l'induction de l'aneuploïdie joue un rôle primordial dans le développement du cancer. Les données disponibles montrent que tous les produits chimiques qui induisent l'aneuploïdie et dont il a été démontré qu'ils provoquent le cancer chez l'homme et/ou les animaux de laboratoire présentent d'autres caractéristiques cancérigènes, telles que la mutagénicité et la clastogénicité, qui sont plus susceptibles de jouer un rôle dans le processus cancérogène. De plus, les aneugènes qui ne possèdent pas ces caractéristiques supplémentaires ne provoquent pas de cancer chez les animaux de laboratoire. L'examen complet présenté dans ce document devrait aider les régulateurs à identifier et à gérer les risques liés aux aneugènes.
- dc.identifier.doi
- https://doi.org/10.1016/j.mrgentox.2019.03.005
- dc.identifier.uri
- https://open-science.canada.ca/handle/123456789/2192
- dc.language.iso
- en
- dc.publisher
- Elsevier
- dc.subject - en
- Health
- Health and safety
- dc.subject - fr
- Santé
- Santé et sécurité
- dc.subject.en - en
- Health
- Health and safety
- dc.subject.fr - fr
- Santé
- Santé et sécurité
- dc.title - en
- Role of aneuploidy in the carcinogenic process: Part 3 of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases
- dc.type - en
- Article
- dc.type - fr
- Article
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