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The TP53 Database: transition from the International Agency for Research on Cancer to the US National Cancer Institute

de Andrade, Kelvin César; Lee, Elaine E; Tookmanian, Elise M; Kesserwan, Chimene A; Manfredi, James J; Hatton, Jessica N; Loukissas, Jennifer K; Zavadil, Jiri; Zhou, Lei; Olivier, Magali; Frone, Megan N; Shahzada, Owais; Longabaugh, William J R; Kratz, Christian P; Malkin, David; Hainaut, Pierre; Savage, Sharon A
PMCID:9090805
PMID: 35352025
ISSN: 1476-5403
CID: 5469202

Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure

Karanović, Sandra; Ardin, Maude; Tang, Zuojian; Tomić, Karla; Villar, Stephanie; Renard, Claire; Venturini, Elisa; Lorch, Adam H; Lee, Daniel S; Stipančić, Želimir; Slade, Neda; Vuković Brinar, Ivana; Dittrich, Damir; Karlović, Krešimir; Borovečki, Fran; Dickman, Kathleen G; Olivier, Magali; Grollman, Arthur P; Jelaković, Bojan; Zavadil, Jiri
Recurrent upper tract urothelial carcinomas (UTUCs) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). Here we delineated the molecular programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe. We applied an integrative multiomics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative microRNA (miRNA) and messenger ribonucleic acid (mRNA) expression profiling, immunohistochemical analysis by tissue microarrays and exome and transcriptome sequencing were performed in UTUC and nontumor tissues. Urinary miRNAs of cases undergoing surgery were profiled before and after tumor resection. Ribonucleic acid (RNA) and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1,862 target mRNAs, involving deregulation of cell cycle, deoxyribonucleic acid (DNA) damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC-specific transcripts were confirmed at the protein level. Exome and transcriptome sequencing of UTUCs revealed AA-specific mutational signature SBS22, with 68% to 76% AA-specific, deleterious mutations propagated at the transcript level, a possible basis for neoantigen formation and immunotherapy targeting. We next identified a signature of UTUC-specific miRNAs consistently more abundant in the patients' urine prior to tumor resection, thereby defining biomarkers of tumor presence. The complex gene regulation programs of AAN-associated UTUC tumors involve regulatory miRNAs prospectively applicable to noninvasive urine-based screening of AAN patients for cancer presence and recurrence.
PMCID:8627473
PMID: 34569060
ISSN: 1097-0215
CID: 5067382

Prioritizing cancer hazard assessments for IARC Monographs using an integrated approach of database fusion and text mining

Barupal, Dinesh Kumar; Schubauer-Berigan, Mary K; Korenjak, Michael; Zavadil, Jiri; Guyton, Kathryn Z
BACKGROUND:Systematic evaluation of literature data on the cancer hazards of human exposures is an essential process underlying cancer prevention strategies. The scope and volume of evidence for suspected carcinogens can range from very few to thousands of publications, requiring a complex, systematically planned, and critical procedure to nominate, prioritize and evaluate carcinogenic agents. To aid in this process, database fusion, cheminformatics and text mining techniques can be combined into an integrated approach to inform agent prioritization, selection, and grouping. RESULTS:We have applied these techniques to agents recommended for the IARC Monographs evaluations during 2020-2024. An integration of PubMed filters to cover cancer epidemiology, key characteristics of carcinogens, chemical lists from 34 databases relevant for cancer research, chemical structure grouping and a literature data-based clustering was applied in an innovative approach to 119 agents recommended by an advisory group for future IARC Monographs evaluations. The approach also facilitated a rational grouping of these agents and aids in understanding the volume and complexity of relevant information, as well as important gaps in coverage of the available studies on cancer etiology and carcinogenesis. CONCLUSION/CONCLUSIONS:A new data-science approach has been applied to diverse agents recommended for cancer hazard assessments, and its applications for the IARC Monographs are demonstrated. The prioritization approach has been made available at www.cancer.idsl.me site for ranking cancer agents.
PMID: 33984576
ISSN: 1873-6750
CID: 4867722

The International Collaboration for Cancer Classification and Research (IC3 R)

Cree, Ian A; Indave, Iciar; Zavadil, Jiri; McKay, James; Olivier, Magali; Kozlakidis, Zisis; Lazar, Alexander J; Hyde, Chris; Holdenrieder, Stefan; Hastings, Ros; Rajpoot, Nasir; de la Fouchardiere, Arnaud; Rous, Brian; Zenklusen, Jean Claude; Normanno, Nicola; Schilsky, Richard L
Gaps in the translation of research findings to clinical management have been recognised for decades. They exist for the diagnosis as well as the management of cancer. The international standards for cancer diagnosis are contained within the World Health Organization (WHO) Classification of Tumours, published by the International Agency for Research on Cancer (IARC) and known worldwide as the WHO Blue Books. In addition to their relevance to individual patients, these volumes provide a valuable contribution to cancer research and surveillance, fulfilling an important role in scientific evidence synthesis and international standard-setting. However, the multidimensional nature of cancer classification, the way in which the WHO Classification of Tumours is constructed, and the scientific information overload in the field pose important challenges for the translation of research findings to tumour classification and hence cancer diagnosis. To help address these challenges, we have established the International Collaboration for Cancer Classification and Research (IC3 R) to provide a forum for the coordination of efforts in evidence generation, standard-setting, and best practice recommendations in the field of tumour classification. The first IC3 R meeting, held in Lyon, France, in February 2019, gathered representatives of major institutions involved in tumour classification and related fields to identify and discuss translational challenges in data comparability, standard-setting, quality management, evidence evaluation, and copyright, as well as to develop a collaborative plan for addressing these challenges. This article is protected by copyright. All rights reserved.
PMID: 32818326
ISSN: 1097-0215
CID: 4567272

Mycotoxin exposure and human cancer risk: A systematic review of epidemiological studies

Claeys, Liesel; Romano, Chiara; De Ruyck, Karl; Wilson, Hayley; Fervers, Beatrice; Korenjak, Michael; Zavadil, Jiri; Gunter, Marc J; De Saeger, Sarah; De Boevre, Marthe; Huybrechts, Inge
In recent years, there has been an increasing interest in investigating the carcinogenicity of mycotoxins in humans. This systematic review aims to provide an overview of data linking exposure to different mycotoxins with human cancer risk. Publications (2019 and earlier) of case-control or longitudinal cohort studies were identified in PubMed and EMBASE. These articles were then screened by independent reviewers and their quality was assessed according to the Newcastle-Ottawa scale. Animal, cross-sectional, and molecular studies satisfied criteria for exclusion. In total, 14 articles were included: 13 case-control studies and 1 longitudinal cohort study. Included articles focused on associations of mycotoxin exposure with primary liver, breast, and cervical cancer. Overall, a positive association between the consumption of aflatoxin-contaminated foods and primary liver cancer risk was verified. Two case-control studies in Africa investigated the relationship between zearalenone and its metabolites and breast cancer risk, though conflicting results were reported. Two case-control studies investigated the association between hepatocellular carcinoma and fumonisin B1 exposure, but no significant associations were observed. This systematic review incorporates several clear observations of dose-dependent associations between aflatoxins and liver cancer risk, in keeping with IARC Monograph conclusions. Only few human epidemiological studies investigated the associations between mycotoxin exposures and cancer risk. To close this gap, more in-depth research is needed to unravel evidence for other common mycotoxins, such as deoxynivalenol and ochratoxin A. The link between mycotoxin exposures and cancer risk has mainly been established in experimental studies, and needs to be confirmed in human epidemiological studies to support the evidence-based public health strategies.
PMID: 33337079
ISSN: 1541-4337
CID: 4718252

Experimental investigations of carcinogen-induced mutation spectra: Innovation, challenges and future directions

Melki, Pamela N; Korenjak, Michael; Zavadil, Jiri
Recent years have witnessed an expansion of mutagenesis research focusing on experimentally modeled genome-scale mutational signatures of carcinogens and of endogenous processes. Experimental mutational signatures can explain etiologic links to patterns found in human tumors that may be linked to same exposures, and can serve as biomarkers of exposure history and may even provide insights on causality. A number of innovative exposure models have been employed and reported, based on cells cultured in monolayers or in 3-D, on organoids, induced pluripotent stem cells, non-mammalian organisms, microorganisms and rodent bioassays. Here we discuss some of the latest developments and pros and cons of these experimental systems used in mutational signature analysis. Integrative designs that bring together multiple exposure systems (in vitro, in vivo and in silico pan-cancer data mining) started emerging as powerful tools to identify robust mutational signatures of the tested cancer risk agents. We further propose that devising a new generation of cell-based models is warranted to streamline systematic testing of carcinogen effects on the cell genomes, while seeking to increasingly supplant animal with non-animal systems to address relevant ethical issues and accentuate the 3R principles. We conclude that the knowledge accumulating from the growing body of signature modelling investigations has considerable power to advance cancer etiology studies and to support cancer prevention efforts through streamlined characterization of cancer-causing agents and the recognition of their specific effects.
PMID: 32522347
ISSN: 1873-135x
CID: 4478422

The IARC Monographs: Updated procedures for modern and transparent evidence synthesis in cancer hazard identification

Samet, Jonathan M; Chiu, Weihsueh A; Cogliano, Vincent; Jinot, Jennifer; Kriebel, David; Lunn, Ruth M; Beland, Frederick A; Bero, Lisa; Browne, Patience; Fritschi, Lin; Kanno, Jun; Lachenmeier, Dirk W; Lan, Qing; Lasfargues, Gérard; Curieux, Frank Le; Peters, Susan; Shubat, Pamela; Sone, Hideko; White, Mary C; Williamson, Jon; Yakubovskaya, Marianna; Siemiatycki, Jack; White, Paul A; Guyton, Kathryn Z; Schubauer-Berigan, Mary K; Hall, Amy L; Grosse, Yann; Bouvard, Véronique; Benbrahim-Tallaa, Lamia; Ghissassi, Fatiha El; Lauby-Secretan, Béatrice; Armstrong, Bruce; Saracci, Rodolfo; Zavadil, Jiri; Straif, Kurt; Wild, Christopher P
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 Programme. 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 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.
PMID: 31498409
ISSN: 1460-2105
CID: 4087592

Experimental identification of cancer driver alterations in the era of pan-cancer genomics

Korenjak, Michael; Zavadil, Jiri
Rapidly accumulating data from large-scale cancer genomics studies have been generating important information about genes and their somatic alterations underlying cell transformation, cancer onset and tumor progression. However, these events are usually defined by using computational techniques, while the understanding of their actual functional roles and impact typically warrants validation by experimental means. Critical information has been obtained from targeted genetic perturbation (gene knock-out) studies conducted in animals, yet these investigations are cost-prohibitive and time-consuming. In addition, the 3R principles (replacement, reduction, refinement) have been set in place to reduce animal use burden and are increasingly observed in many areas of biomedical research. Consequently, the focus has shifted to new designs of innovative cell-based experimental models of cell immortalization and transformation in which the critical cancer driver events can be introduced by mutagenic insult and studied functionally, at the level of critical phenotypic readouts. From these efforts, primary cell-based selective barrier bypass models of cell immortalization have emerged as an attractive system that allows studies of the functional relevance of acquired mutations as well as their role as candidate cancer driver events. In this review, we provide an overview of various experimental systems linking carcinogen exposure-driven cell transformation with the study of cancer driver events. We further describe the advantages and disadvantages of the currently available cell-based models while outlining future directions for in vitro modelling and functional testing of cancer-driver events.
PMID: 31594033
ISSN: 1349-7006
CID: 4129622

Experimental Delineation of Mutational Signatures Is an Essential Tool in Cancer Epidemiology and Prevention

Zavadil, Jiri; Rozen, Steven G
Advances in experimental modeling of the mutational signatures of environmental exposures and endogenous mutagenic processes will elucidate the role of mutagenesis in cancer, facilitate carcinogen classification, and enable new molecular cancer epidemiology studies.
PMID: 31509385
ISSN: 1520-5010
CID: 4088002

Characterising Mutational Spectra of Carcinogens in the Tumour Suppressor Gene TP53 Using Human TP53 Knock-in (Hupki) Mouse Embryo Fibroblasts

Hölzl-Armstrong, Lisa; Kucab, Jill E; Korenjak, Michael; Luijten, Mirjam; Phillips, David H; Zavadil, Jiri; Arlt, Volker M
DNA in dividing cells is prone to mutagenesis, with mutations making key contributions to human disease including cancer. The tumour suppressor gene TP53 is the most frequently mutated gene in human tumours. Here, we present a robust protocol for studying TP53 mutagenesis utilising human TP53 knock-in (Hupki) mouse embryonic fibroblasts (HUFs). In the HUF immortalisation assay (HIMA), primary HUFs are treated with known or suspected carcinogens at 3% oxygen and then transferred to 20% atmospheric oxygen to induce senescence. Cells containing mutations (e.g., in TP53) that allow bypassing of senescence eventually emerge as immortalised clonal cell lines after 2-3 months of serial passaging. As not all immortalised HUF cells contain TP53 mutations, we developed a Nutlin-3a counter-screen to select for TP53-mutated clones prior to sequencing. TP53 mutation spectra generated can be compared with those of human tumours recorded in the International Agency for Research on Cancer TP53 mutation database. Environmental mutagens that have demonstrated and validated the utility of the HIMA include ultraviolet radiation, aristolochic acid, and benzo[a]pyrene. The TP53 mutation patterns induced by these mutagens in the HIMA corresponded to those found in human tumours from patients exposed to these mutagens. The approach presented helps to deepen our understanding of human cancer aetiology.
PMID: 31766274
ISSN: 2409-9279
CID: 4237612