Gilbert W. Beebe Symposium
This year’s National Academies’ Gilbert W. Beebe Symposium will focus on research questions related to the Chernobyl accident. DCEG investigators are playing a key role in developing the agenda.
In the five years since our last review of the accomplishments of the Chernobyl Research Unit, DCEG investigators have begun to realize the full potential of cutting edge molecular and genetic epidemiological methods to expand our knowledge on the relationship between ionizing radiation and cancer. In the years ahead many new initiatives and those already underway should yield important results.
Investigating Heritable Effects
To understand how radiation exposure of parents may affect future offspring, experts in the Radiation Epidemiology Branch (REB) have launched a study of parent-child trios in which at least one parent was exposed to Chernobyl radiation as a clean-up worker and/or evacuee from a contaminated area. The effort—known as the Chernobyl TRIO study—will examine germline de novo mutation and recombination rates, as well as germline minisatellite mutations, copy number alterations, and variations in telomere length. This is intended to investigate the effects of radiation in children, and when possible, map findings to possible parental origin of the chromosome. In areas of Ukraine and Belarus exposed to fallout from Chernobyl, some early studies have reported excess minisatellite mutations among children born after the accident. The Chernobyl TRIO study will be the first study with adequate statistical power to detect effects of the magnitude expected based on animal data. Also unique to this study is the composition of low doses and protracted exposures associated with nuclear accidents and environmental exposures.
“Ionizing radiation is one of the oldest known carcinogens. However, our ability to trace its effects to future generations has been limited by the scope of our research tools. Today, these exacting instruments allow us to examine the influence of this exposure on the next generation,” said Stephen J. Chanock, M.D., DCEG Director and co-investigator on the Chernobyl TRIO study.
In collaboration with the Research Center for Radiation Medicine in Ukraine, investigators are collecting biological samples, epidemiologic data, reconstructing parental gonadal doses, and applying state-of-the-art genomic technologies to characterize the genomes of 450 trios of parents with preconception doses and their unexposed offspring.
Ongoing Study of Elevated Thyroid Cancer Risks
Thyroid cancer remains one of the major health effects of the accident, particularly among those exposed to radioactive fallout as children or adolescents. Studies of this population, carried out by REB and the Institute of Endocrinology and Metabolism in Ukraine, have found a strong, linear relationship between individual I-131 thyroid dose and risk of thyroid cancer, which remains elevated two decades after exposure. The investigators estimate that half of incident cancers in the cohort can be attributed to I-131 exposure. A parallel study of thyroid cancer in Belarus found a similarly strong association. The new cycle of thyroid screening in the Ukrainian cohort, just completed, will extend follow up through 29 years after the accident.
The Search for Genetic Signatures of Radiation Exposure
To date, the molecular signatures, as well as the mechanisms underlying the association of radiation and thyroid cancer, remain poorly understood. Previous DCEG studies have reported several types of somatic alterations and altered expression of certain genes linked with I-131 doses. Following up on these focused genetic studies, DCEG researchers are applying whole genome sequencing techniques to thyroid tumor tissues, adjacent normal tissues, and blood samples obtained through the Chernobyl Tissue Bank to better understand the genetic makeup of this malignancy.
“Our study amounts to the largest set of genomic data on radiation-related thyroid cancer in the world,” said Amy Berrington de González, D.Phil., Chief of REB. “This is a unique population where a high proportion of the cancers are likely related to radiation, and we have very well characterized exposure information.”
Using radiation dose and clinical and demographic characteristics, the researchers will map the somatic and germline landscape of these tumors, explore gene-radiation interactions, and investigate the role of copy number alterations, genetic mosaicism, mRNA and miRNA expression, DNA methylation and telomere length in the etiology of this malignancy. The result will be an integrated snapshot of the genomic, transcriptomic, and epigenomic characteristics of tumors in 450 exposed and 550 unexposed individuals. The study will confirm findings in formalin-fixed, paraffin-embedded samples of the same approximate size. The study has the potential to provide unique insights into the mechanisms of radiation carcinogenesis and to generate a rich data resource for investigating radiation-induced genetic changes.
Read more articles from the spring 2016 issue of Linkage newsletter.