PO.PS01.08 · 人群科学

区分切尔诺贝利核电站事故后辐射诱发的甲状腺癌与散发性甲状腺癌

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

该海报暂无可下载的资料 AACR 官方页面

作者与单位 Authors & Affiliations

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

中文摘要

1986年切尔诺贝利事故的放射性沉降物增加了儿童期暴露后罹患甲状腺乳头状癌（PTC）的风险。辐射诱发的肿瘤与散发性肿瘤无法通过临床特征、组织学特征或已知的COSMIC特征加以区分。最近一项分析研究了在切尔诺贝利暴露者和未暴露者中产生PTC致癌驱动因素的DNA损伤模式，因为此类模式反映了DNA修复机制，例如健康细胞进行高效的DNA双链断裂（DSB）修复而不发生实质性的DNA丢失。由两个断裂点产生且断裂点获得/丢失<20个碱基对（bp）的融合/结构变异（SV）驱动的PTC（Fusion 2B<20bp）与由辐射所致相一致（随辐射剂量增加频率升高，性别分布均匀），而具有≥3个断裂点且断裂点丢失≥1000 bp的融合/SV驱动的PTC（Fusion 3B≥1000bp）以及BRAF V600E驱动的PTC则未表现出辐射剂量关联，并呈现明显的女性优势。为研究其他融合/SV驱动类别的辐射剂量和性别分布并重复既往报告，我们重建了甲状腺辐射剂量，并对244例经组织学确认的PTC进行了测序（见表）。与BRAF V600E-PTC相比，所有断裂点丢失<1000 bp的融合/SV驱动PTC的辐射剂量均显著更高（P=0.0084至7.1×10^-10），无论融合/SV驱动断裂点的数量如何；而断裂点丢失≥1000 bp的融合/SV驱动PTC的剂量则相当低，尽管样本数较小。仅Fusion 2B<20bp-PTC重复组与BRAF V600E-PTC相比女性优势较低（67.1% vs. 79.0%，P=0.068）。这些结果提供了证据表明，在此剂量范围内，融合/SV驱动断裂点处的获得/丢失量比DNA DSB的数量是区分辐射诱发肿瘤与散发性肿瘤更有信息量的特征。各PTC致癌驱动类别的性别和辐射剂量分布性别甲状腺辐射剂量（mGy）女性男性未暴露 1-99 100-199 200-499 500-999 ≥1000 驱动类别总计N（%） N（%） P* N（%） N（%） N（%） N（%） N（%） N（%）均值中位数 P* 2个断裂、两个断裂点均<20 bp（既往发表） 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个断裂、两个断裂点均<20 bp（重复组） 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个断裂、两个断裂点均<1000 bp（新类别）† 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个断裂、≥1个断裂点丢失≥1000 bp（新类别） 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个断裂、所有断裂点均<20 bp（新类别） 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个断裂、所有断裂点均<1000 bp（新类别）† 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个断裂、≥1个断裂点丢失≥1000 bp（既往发表） 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个断裂、≥1个断裂点丢失≥1000 bp（重复组） 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 大片段缺失（≥1000 bp）（新类别） 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（既往发表） 162 124（76.5%） 38（23.5%）参照 30（18.5%） 88（54.3%） 28（17.3%） 11（6.8%） 2（1.2%） 3（1.9%） 93.6 48.9 参照 BRAF V600E（重复组） 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值来自纳入性别、甲状腺辐射剂量及PTC发病年龄协变量的多分类logistic回归模型。† 包括≥1个断裂点具有20-999 bp的获得/丢失

查看英文原文 English 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.

← 返回 AACR 2026 检索