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Investigation of the Relationship Between Radiation Dose and Gene Mutations and Fusions in Post-Chernobyl Thyroid Cancer. J Natl Cancer Inst 2018 04 01;110(4):371-378

Date

11/23/2017

Pubmed ID

29165687

Pubmed Central ID

PMC6059206

DOI

10.1093/jnci/djx209

Scopus ID

2-s2.0-85052518227   16 Citations

Abstract

Background: Exposure to ionizing radiation during childhood is a well-established risk factor for thyroid cancer. However, the genetic mechanisms of radiation-associated carcinogenesis remain not fully understood.

Methods: In this study, we used targeted next-generation sequencing and RNA-Seq to study 65 papillary thyroid cancers (PTCs) from patients in the Ukrainian-American cohort with measurement-based iodine-131 (I-131) thyroid doses received as a result of the Chernobyl accident. We fitted linear regression models to evaluate differences in distribution of risk factors for PTC according to type of genetic alteration and logistic regression models to evaluate the I-131 dose response. All statistical tests were two-sided.

Results: Driver mutations were identified in 96.9% of these thyroid cancers, including point mutations in 26.2% and gene fusions in 70.8% of cases. Novel driver fusions such as POR-BRAF, as well as STRN-ALK fusions that have not been implicated in radiation-associated cancer before, were found. The mean I-131 dose in cases with point mutations was 0.2 Gy (range = 0.013-1.05 Gy), statistically significantly lower than 1.4 Gy (range = 0.009-6.15 Gy) for cases with fusions (P < .001). No driver point mutations were found in tumors from individuals who received more than 1.1 Gy of radiation. Relative to tumors with point mutations, the proportion of tumors with gene fusions increased with radiation dose, reaching 87.8% among individuals exposed to 0.3 Gy or higher. With a limited study sample size, the estimated odds ratio at 1 Gy was 20.01 (95% confidence interval = 2.57 to 653.02, P < .001). In addition, after controlling for I-131 dose, we found higher odds ratios for gene fusion-positive PTCs associated with several specific demographic and geographic features.

Conclusions: Our data provide support for a link between I-131 thyroid dose and generation of carcinogenic gene fusions, the predominant mechanism of thyroid cancer associated with radiation exposure from the Chernobyl accident.

Author List

Efanov AA, Brenner AV, Bogdanova TI, Kelly LM, Liu P, Little MP, Wald AI, Hatch M, Zurnadzy LY, Nikiforova MN, Drozdovitch V, Leeman-Neill R, Mabuchi K, Tronko MD, Chanock SJ, Nikiforov YE

Author

Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Biomarkers, Tumor
Calmodulin-Binding Proteins
Carcinoma, Papillary
Chernobyl Nuclear Accident
Child
Child, Preschool
Cohort Studies
Cytochrome P-450 Enzyme System
Female
Follow-Up Studies
Gene Fusion
High-Throughput Nucleotide Sequencing
Humans
Infant
Iodine Radioisotopes
Male
Membrane Proteins
Mutation
Neoplasms, Radiation-Induced
Nerve Tissue Proteins
Oncogene Proteins, Fusion
Prognosis
Proto-Oncogene Proteins B-raf
Radiation Dosage
Thyroid Neoplasms
Young Adult
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d