PO.PS01.08 · 人群科学

Distinguishing radiation-induced from sporadic thyroid cancers after the Chornobyl nuclear power plant accident

编号 6293 展板 23 时间 4/21 02:00–05:00 区域 Section 34 主讲 Lindsay Morton, PhD

分会场 Genetic Epidemiology 2: Pathway Analysis, Sequencing, Functional Genetics / Family and Hereditary Studies

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作者与单位

Danielle M. Karyadi¹, Tetiana I. Bogdanova², Stephen W. Hartley¹, Vladimir Drozdovitch¹, Sergii Masiuk³, Belynda Hicks⁴, Kristine Jones⁴, Amy Hutchinson⁴, Petra Lenz⁴, Maria Brown⁴, Aaron M. Rozeboom⁴, Elizabeth K. Cahoon¹, Mykola Chepurny³, Liudmyla Yu Zurnadzhy², Vibha Vij¹, Cari M. Kitahara¹, Michael Dean¹, Gayle E. Woloschak⁵, Dale A. Ramsden⁶, Mykola D. Tronko⁷, Stephen J. Chanock⁸, Lindsay M. Morton¹

¹National Cancer Inst. Div. of Cancer Epidemiology & Genetics, Bethesda, MD,²2 Laboratory of Morphology of the Endocrine System, V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine,³Radiological Protection Laboratory, State Institution National Research Center for Radiation Medicine Hematology and Oncology of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine,⁴Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD,⁵Northwestern University Feinberg School of Medicine, Chicago, IL,⁶98 Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC,⁷109 Department of Fundamental and Applied Problems of Endocrinology, V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine,⁸Sect. Head & Director, CGF/ATC, National Cancer Institute, Rockville, MD

摘要 Abstract

Radioactive fallout from the 1986 Chornobyl accident increased papillary thyroid carcinoma (PTC) risk after childhood exposure. Radiation-induced versus sporadic tumors cannot be distinguished by clinical characteristics, histologic features, or known COSMIC signatures. A recent analysis examined the pattern of DNA damage that generated PTC oncogenic drivers from Chornobyl-exposed and unexposed individuals because such patterns reflect DNA repair mechanisms, e.g., healthy cells engage efficient DNA double-strand break (DSB) repair without substantial DNA loss. PTC with fusion/structural variant (SV) drivers generated from two breakpoints and <20 basepairs (bp) breakpoint gain/loss (Fusion 2B<20bp ) were consistent with having been caused by radiation (higher frequency with increasing radiation dose, even distribution by sex), whereas fusion/SV-driven PTC with ≥3 breakpoints and ≥1000 bp breakpoint loss (Fusion 3B≥1000bp ) and BRAF V600E -driven PTC exhibited no radiation dose association and strong female predominance. To investigate radiation dose and sex distributions for additional fusion/SV driver categories and replicate the previous report, we reconstructed thyroid radiation doses and sequenced 244 histologically-confirmed PTCs (Table). Radiation doses were significantly higher for all fusion/SV-driven PTC with <1000 bp breakpoint loss (P=0.0084 to 7.1×1 -10 ), regardless of the number of fusion/SV driver breakpoints, compared with BRAF V600E -PTC, while doses were comparably low for fusion/SV-driven PTC with ≥1000 bp breakpoint loss, albeit based on small numbers. Only the Fusion 2B<20bp -PTC replication group had a lower female predominance compared with BRAF V600E -PTC (67.1% vs. 79.0%, P=0.068). These results provide evidence that the amount of gain/loss at the fusion/SV driver breakpoint is a more informative feature than the number of DNA DSBs for distinguishing radiation-induced from sporadic tumors in this dose range. Distribution of sex and radiation dose by PTC oncogenic driver category Sex Thyroid radiation dose (mGy) Female Male Unexposed 1-99 100-199 200-499 500-999 ≥1000 Driver category Total N (%) N (%) P* N (%) N (%) N (%) N (%) N (%) N (%) Mean Median P* 2 breaks, <20 bp at both breakpoints (Previously published) 66 35 (53.0%) 31 (47.0%) 1.34x10 -4 3 (4.5%) 15 (22.7%) 14 (21.2%) 20 (30.3%) 6 (9.1%) 8 (12.1%) 315.2 207.7 8.39x10 -8 2 breaks, <20 bp at both breakpoints (Replication) 73 49 (67.1%) 24 (32.9%) 0.068 0 (0.0%) 22 (30.1%) 15 (20.5) 16 (21.9%) 9 (12.3%) 11 (15.1%) 361.7 185.5 7.10x10 -10 2 breaks, <1000 bp at both breakpoints (New category)† 34 26 (76.5%) 8 (23.5%) 0.72 6 (17.6%) 9 (26.5%) 8 (23.5) 5 (14.7%) 3 (8.8%) 3 (8.8%) 230.4 130.5 5.46x10 -4 2 breaks, ≥1000 bp loss at ≥1 breakpoint (New category) 7 5 (71.4%) 2 (28.6%) 0.60 1 (14.3%) 4 (57.1%) 2 (28.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 58.9 58.2 0.42 ≥3 breaks, <20 bp at all breakpoints (New category) 4 3 (75.0%) 1 (25.0%) 0.87 0 (0.0%) 2 (50.0%) 0 (0.0%) 1 (25.0%) 0 (0.0%) 1 (25.0%) 360.8 203.4 0.0084 ≥3 breaks, <1000 bp at all breakpoints (New category)† 13 11 (84.6%) 2 (15.4%) 0.60 1 (7.7%) 4 (30.8%) 3 (23.1%) 1 (7.7%) 2 (15.4%) 2 (15.4%) 341.6 127.2 4.21x10 -5 ≥3 breaks, ≥1000 bp loss at ≥1 breakpoint (Previously published) 32 30 (93.8%) 2 (6.3%) 0.075 12 (37.5%) 15 (46.9%) 4 (12.5%) 0 (0.0%) 1 (3.1%) 0 (0.0%) 62.1 35.6 0.12 ≥3 breaks, ≥1000 bp loss at ≥1 breakpoint (Replication) 5 4 (80.0%) 1 (20.0%) 0.99 1 (20.0%) 3 (60.0%) 0 (0.0%) 1 (20.0%) 0 (0.0%) 0 (0.0%) 77.5 52.1 0.70 Large deletion (≥1000 bp) (New category) 13 10 (76.9%) 3 (23.1%) 0.87 3 (23.1%) 5 (38.5%) 1 (7.7%) 0 (0.0%) 2 (15.4%) 2 (15.4%) 273.3 86.1 0.0017 BRAF V600E (Previously published) 162 124 (76.5%) 38 (23.5%) Reference 30 (18.5%) 88 (54.3%) 28 (17.3%) 11 (6.8%) 2 (1.2%) 3 (1.9%) 93.6 48.9 Reference BRAF V600E (Replication) 95 79 (83.2%) 16 (16.8%) 11 (11.6%) 55 (57.9%) 17 (17.9%) 6 (6.3%) 5 (5.3%) 1 (1.1%) 114.9 52.1 * P-values were derived from a polytomous logistic regression model including covariates for sex, thyroid radiation dose, and age at PTC.† includes ≥1 breakpoint with 20-999 bp gain/loss

利益披露 Disclosure

D. M. Karyadi, None.. T. I. Bogdanova, None.. S. W. Hartley, None.. V. Drozdovitch, None.. S. Masiuk, None.. B. Hicks, None.. K. Jones, None.. A. Hutchinson, None.. P. Lenz, None.. M. Brown, None.. A. M. Rozeboom, None.. E. K. Cahoon, None.. M. Chepurny, None.. L. Y. Zurnadzhy, None.. V. Vij, None.. C. M. Kitahara, None.. M. Dean, None.. D. A. Ramsden, None.. M. D. Tronko, None.. L. M. Morton, None.

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