Environmental Mutagenesis & Genomics Society
Virtual Annual Meeting
September 22-25, 2021
Virtual Meeting, Real Science
All times in Eastern Daylight Time.
THURSDAY, SEPTEMBER 23, 2021
12:15 PM -1:45PM (EDT) | Linking Mutational Spectra to Endogenous and Exogenous Exposures
Sponsored by TwinStrand Biosciences
Chairs: Dan Roberts, PhD, Charles River Laboratories, Skokie, IL (U.S.) SNI Co-Chair: Eunnara Cho,, Health Canada, Ottawa (CA)
Mutational signatures have become indispensable tools for studying mutational processes underlying carcinogenesis. Increasing number of mutational signatures are being linked to endogenous and exogenous exposures, allowing new insights into their contribution to cancer etiologies. Mutational signatures form as the result of DNA damage induced by genotoxicants and the cellular repair mechanisms; therefore, mutational spectra of genotoxicants can not only link chemical exposures to pathogenesis, but also provide mechanistic information regarding chemical mutagenicity. As NGS technologies advance and become more accessible, analysis of mutational spectra of chemicals will become an integral part of genotoxicity assessment. The goals of this symposium are to highlight recent advances in identifying and understanding mutational signatures associated with chemical exposures and endogenous processes and to discuss the utility of mutational spectra in genetic toxicology.
12:15 PM to 12:40 PM | Utility of Mutational Spectra to Identify Tumor Origin
Steve Rozen, PhD, Duke-NUS Medical School, Singapore, Singapore (S.G.)
12:40 PM to 1:05 PM | Application of Mutational Signatures of Carcinogens as Biomarkers of Cancer
Bogdan Fedeles, PhD, and John Essigmann, PhD, Massachusetts Institute of Technology, Cambridge, MA (U.S.)
1:05 PM to 1:25 PM | Somatic Mutations, Genome Mosaicism, Aging and Disease
Jan Vijg, PhD, Albert Einstein College of Medicine, New York City, NY (U.S.)
1:25 PM to 1:45 PM | Glycidamide Hypermutation in Single-Stranded DNA is Dependent on Translesion Synthesis
Katie Hudson, PhD, National Institute of Environmental Health Sciences, Research Triangle Park, NC, (U.S.)
12:15 PM -1:45 PM | Epigenetics: From the Lab Bench to the Regulator’s Desk
Chair: Jaclyn Goodrich, PhD, University of Michigan School of Public Health, Ann Arbor, MI (U.S.) Co-Chair: Isabelle Miousse, PhD, University of Arkansas for Medical Sciences, Little Rock, AR (U.S.) SNI Co-Chair: Sumira Phatak, Utah State University, Logan, UT (U.S.)
Exposure to environmental toxicants is associated with changes in the epigenome, which in turn orchestrate metabolic adaptation. Changes in the epigenome can be detected at very low levels of exposure, including exposure to non-genotoxic toxicants. It therefore bears great promise as a tool for risk assessment. However, major challenges remain before it can be fully incorporated into risk assessment. Challenges include establishing replicable epigenetic biomarkers of exposure and establishing links between these epigenomic alterations and disease. In this workshop, we use cancer as an example to discuss these challenges and avenues to overcome them. We first present evidence for the role of epigenetics in cancer and for long-term changes to the epigenome by exposure. We then discuss epigenetics from a regulator’s viewpoint. The session will conclude with a moderated panel discussion. During this discussion, gaps in research will be identified that will be needed in order to move the field towards incorporating epigenomic analysis into our risk assessment tool kit.
12:15 PM to 12:35 PM | The Role of Epigenetics in Cancer
Trevor Archer, PhD, National Institute of Environmental Health Sciences, Research Triangle Park, NC (U.S.)
12:35 PM to 12:55 PM | Long-term Programming of Epigenetic Changes From Exposure
Lindsey Trevino, PhD, City of Hope, Duarte, CA (U.S.)
12:55PM to 1:15 PM | Epigenetics in Risk Assessment: Clarity or Confusion?
Brian Chorley, PhD, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC (U.S.)
1:15PM to 1:45 PM | Moderated Panel Discussion: Where Do We Go From Here?
Cont. THURSDAY, SEPTEMBER 23, 2021
3:30 PM -5:00PM | Genetic Determinants of Disease Risk from Environmental DNA Damage
Chair: Kara Bernstein, PhD, University of Pittsburgh, PA (U.S.) Co-chair & SNI Co-Chair: Khadijeh Alnajjar, PhD, University of Arizona, Tucson, AZ (U.S.)
Our cells are constantly responding to an onslaught of environmental toxicants that threaten the integrity of our genome. With the decreased cost of DNA sequencing and direct to consumer DNA testing, how one’s environmental exposures is compounded by our unique genetic makeup is going to revolutionize precision medicine and risk assessment. This symposium entitled “Variants of Unknown Significance in DNA Repair Genes and Disease Risk” will address current topics of how our environmental exposures are influenced by our genetics leading to different diseases, such as cancer. We will cover different types of DNA damage and how individual DNA repair variants of unknown significance should be considered in determining disease risk.
3:30 PM to 3:50 PM | Variants of Unknown Significance in DNA Repair Genes and Disease Risk
Kara Bernstein, PhD, University of Pittsburgh, Pittsburg, PA (U.S.)
3:50 PM to 4:15 PM | Variants of Uncertain Significance in Lynch Syndrome Patients
Aishwarya Prakash, PhD, University of South Alabama, Mobile, AL (U.S.)
4:15 PM to 4:35 PM | Base Excision Repair Variants in Human Disease
Joann Sweasy, PhD, Arizona State University, Tempe, AZ (U.S.)
4:35 PM to 5:00 PM | Variants of Unknown Significance in MUTYH Unveil Features of Enzyme Function and Potential Impact in Cancer
Sheila David, PhD, University of California, Davis, CA (U.S.)
FRIDAY, SEPTEMBER 24, 2021
12:15 PM – 1:45PM | Interpretation of Genotoxicity Dose-response Information in a Human Health Context
Chair: Leslie Recio, PhD, DABT, Integrated Laboratory Systems, Inc., Research Triangle Park, NC, (U.S.) Co-Chair: Paul White, PhD, Health Canada, Ottawa (CA) SNI Co-Chair: Marc Beal, PhD, Health Canada, Ottawa (CA)
Genetic toxicology assessments are performed to protect human health, which makes the human relevance of genetic toxicology data an issue of critical importance. There are two overarching strategies to make genetic toxicology assessments human-relevant: 1) selection of models integrated with dosimetrics to make the experimentally derived data as human-relevant as possible, and 2) through post-hoc evaluation of human-relevance and the application of safety/uncertainty factors for interpretation of dose-response data in a risk assessment context. This symposium will provide a high level overview of approaches to design and implement experimental strategies to maximize human relevance. This will include discussion of the importance of adding genotoxicity assessments in human cell models to regulatory genetic toxicology decision making, the utility of different endpoints, along with the application of physiologically-based pharmacokinetic modeling for interspecies extrapolation, and lastly, the choice of appropriate uncertainty factors for human-relevant interpretation of in vivo dose-response data.
12:15 PM to 12:35 PM | Genotoxicity Assessments in Human Cell and Tissue Models as New Alternative Methods to in Vivo Models in Genetic Toxicology
Leslie Recio, PhD, Integrated Laboratory Systems, Inc., Research Triangle Park, NC, (U.S.)
12:35 PM to 12:50 PM | In Vitro to In Vivo Extrapolation Incorporating Toxicokinetics
Marc Beal, PhD, Health Canada, Ottawa (CA) and Katie Paul Friedman, PhD, US Environmental Protection Agency, Research Triangle Park, NC (U.S.)
12:50 PM to 1:10 PM | PBPK Modeling and In Vitro to In Vivo Extrapolation (IVIVE) Modeling
Shannon Bell, PhD, Integrated Laboratory Systems, Inc., Research Triangle Park, NC, (U.S.)
1:10 PM to 1:25 PM | Effect of Animal Life-Stage on Chemically-Induced Mutagenicity
Robert Heflich, PhD, FDA National Center for Toxicological Research, Jefferson, AR (U.S.)
1:25 PM to 1:45 PM | Quantitative Interpretation of In Vivo Mutagenicity Dose-Response Data; UFs for Calculation of Human Exposure Limits
Paul White, PhD, Health Canada, Ottawa, ON (CA)
Cont. FRIDAY, SEPTEMBER 24, 2021
3:30 PM – 5:00 PM | Personalized Epidemiology: Assessment of Individual Cancer Risk Using Compendiums of Damaging Endogenous and Environmental Processes
Chair: Clint Valentine, PhD, TwinStrand Biosciences, Seattle, WA (U.S.) Co-Chair: Fang Yin Lo, PhD, TwinStrand Biosciences, Seattle, WA (U.S.)
In the last decade, we observed an increase in large cohort studies that are successfully mining patterns of endogenous and environmental mutagenic processes from clonally expanded laboratory or patient samples. The utilities of these patterns are beginning to be revealed, and research is now under way to better understand if these patterns can be used as a biomarker of cancer risk for the individual. As we look towards the future, we would like to explore how validated patterns of mutagenesis, with tangible etiologies extracted from large cohorts, can be leveraged for longitudinal personalized cancer risk assessment.
3:30 PM to 3:50 PM | Mutational Signatures in Experimental Models: From Induced Pluripotent Stem Cells to Tissue-Derived Organoids
Jill Kucab, PhD, King's College London, London, (U.K)
3:50 PM to 4:15 PM | Non-invasive Detection of Aristolochic Acid Exposure Using Ultra-Sensitive Duplex Sequencing
Arnoud Boot, PhD, Duke-NUS Medical School, Singapore, (S.G.)
4:15 PM to 4:35 PM | The Mutational Signature Profile of Known and Suspected Human Carcinogens in Mice
Laura Riva, PhD, Sanger Institute, Hinxton, Cambridgeshire (U.K.)
4:35 PM to 5:00 PM | The Impact of PUVA Therapy for Skin Disorders on Renal Carcinogenesis: A Genome-Wide, Multi-System Study
Jiri Zavadil, PhD, International Agency for Research on Cancer, Lyon, France.
SATURDAY, SEPTEMBER 25, 2021
12:15 PM -1:45PM | Germ Cell Mutation and Developmental Mosaicism: Potential Health Implications
Chair: Jonatan Axelsson, PhD Co-Chair: Carole Yauk, PhD, Univ. of Ottawa, Ottawa (CA), NI Co-Chair: Danielle LeBlanc
Mutations have a causal role in genetic disease and cancer. In addition, they have the ability to induce mosaicism; the existence of genetically distinct cell populations in one organism. Mutations or mosaicism that occur de novo, in the germline, the placenta or in early development, are of particular concern due to their influence on the health of the succeeding generation. Indeed, mosaicism has been associated with multiple genetic diseases and, when present in germ cells, can lead to embryonic lethal disorders. The advancement of whole genome sequencing has enabled the efficient characterization of mutations as well as the identification and quantification of mosaicism in somatic and germline tissues. Speakers will present their findings on de novo mutation rate in human cohorts with different ancestral backgrounds, the burden of somatic mutation and mosaicism in human placentas, and the risks associated with stable mosaic mutations in sperm.
12:15 PM to 12:45 PM | De Novo Mutations and Spectra in Different Ancestries - Reductions in People With Lower Mutagen Exposure
Michael Kessler, PhD Health Sciences Facility, MD, (U.S.)
12:45 PM to 1:15 PM | Germ cell mutation and developmental mosaicism: potential health implications
Amelia Wallace, PhD, University of Utah, Salt Lake City, UT, (U.S.)
1:15 PM to 1:45 PM | Temporal stability of human sperm mosaic mutations results in life-long threat of transmission to offspring
Xiaoxu Yang, PhD, University of California, San Diego, La Jolla, CA, (U.S.)
Cont. SATURDAY, SEPTEMBER 25, 2021
3:30PM -5:00PM | Development and Application of Genomic Approaches to Evaluate Human Cancer Risk
Chair: Sheroy Minocherhomji, PhD, Amgen, Thousand Oaks, CA (U.S.) Co-Chair: Clint Valentine, PhD, TwinStrand Biosciences, Seattle, WA (U.S.)
Current approaches to assess human cancer risk of chemicals, environmental agents and therapeutics continue to rely on decades old approaches of assessing mutagenicity in bacteria (Ames assay), cytogenetic effects and chronic rodent bioassays. More contemporary genomic tools focused on transcriptomic and DNA sequencing are affording a more direct and higher resolution view to the impact of chemical exposures on the genome, and in turn providing a more sensitive, translationally relevant, and mechanistically based approach to assess cancer risk. This symposium aims to provide a current view to a number of workstreams focused on validating these genomic tools and showcasing their application to evaluating genotoxicity and human cancer risk.
3:30 PM to 3:45 PM | CarcSeq Quantification of Cancer Drive Mutations: Early Biomarker of Clonal Expansion for Prediction of Future Neoplasia
Barbara Parsons, PhD, US-FDA NCTR, Jefferson, AR (U.S.)
3:45 PM to 4:00 PM | Genomic Instability: A Key Characteristic of Carcinogens and Methods to Evaluate It
Sheroy Minocherhomji, PhD, Amgen, Thousand Oaks, CA (U.S.)
4:00 PM to 4:15 PM | Towards Reduction and Replacement of The 2-year Rodent Bioassay Using Genomic Approaches: Update From eSTAR and Impact on ICH S1
Chris Corton, PhD, U.S. Environmental Protection Agency, Washington, DC (U.S.)
4:15 PM to 4:30 PM | Detecting low-frequency clonally expanded cell populations using Duplex Sequencing as potential biomarkers of nongenotoxic carcinogens and preneoplastic events
Keith Tanis, PhD, Merck Research Laboratories, West Point, PA (U.S.)
4:30 PM to 4:45 PM | Optimal Methodological design for Duplex Sequencing™ In TK6 Cells Determined Through a Time and Concentration Response Analysis Following ENU Treatment
Eunnara Cho, Health Canada, Ottawa, ON (CA)
4:45 PM to 5:00 PM | Moderated Panel Discussion