1 / 41

Vladimir Saenko Department of Health Risk Control Atomic Bomb Disease Institute

Vladimir Saenko Department of Health Risk Control Atomic Bomb Disease Institute Nagasaki University Graduate School of Biomedical Sciences. 10 th AOTA Congress October 21-24, Bali, Indonesia. Radiation and thyroid carcinogenesis. Content Radiation epidemiology of thyroid cancer

zody
Download Presentation

Vladimir Saenko Department of Health Risk Control Atomic Bomb Disease Institute

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Vladimir Saenko Department of Health Risk Control Atomic Bomb Disease Institute Nagasaki University Graduate School of Biomedical Sciences 10th AOTA Congress October 21-24, Bali, Indonesia Radiation and thyroid carcinogenesis

  2. Content • Radiation epidemiology of thyroid cancer • Pathology (Chernobyl) • Clinical prognosis (Chernobyl) • Molecular characteristics (Chernobyl)

  3. Radiation exposure of the thyroid at young age is the most clearly defined environmental factor associated with thyroid cancer I. Radiation epidemiology • External radiation exposure • A-bomb hibakusha • Marshall Islanders (fall-out) • Children exposed to EBT • Internal radiation exposure • Therapeutic radioiodine • Hanford (fall-out) • Chernobyl ERR/Gy~7.7 [1.1 – 32] OR at 1 Gy~5.5 – 8.4 [ERR/Gy 1.9 – 19] External exposure Chernobyl (0-17 y.o.) Relative risk Thyroid dose (Gy) E.Ron 2002 V.Ivanov 2010

  4. 26 April 1986 the accident at the Chernobyl nuclear power plant Radioactive substance release -13 EBq: 131 I - 1.8 Ebq 137Cs - 0.085 Ebq 90Sr - 0.01 Ebq Pu isotopes - 0.003 EBq More than 200 000 sq km of Europe were contaminated with > 37 kBq/sq m of 137Cs Over 70 % of this area was in the three most affected countries, Belarus, Russia and Ukraine. The Chernobyl Forum: 2003–2005, IAEA

  5. Estimated average thyroid doses to children and adolescents around Chernobyl UNSCEAR 2008 Report Annex D

  6. Belarus Ukraine Three countries Russia Incidence of thyroid cancer in the residents of radiocontaminated territories

  7. Incidence of thyroid cancer diagnosed in 1986-2002 No. of cases Age at exposure (yr) Belarus Russian Ukraine Total Federation 0-14 1,711 349 1,762 3,822 15-17 299 134 582 1,015 Total 2,010 483 2,344 4,837 Health Effects of the Chernobyl Accident and Special Health Care Programmes Report of the UN Chernobyl Forum, 2006 UNSCEAR 2008 Report, Annex D: Over 6,000 thyroid cancers by 2006

  8. Dose-dependent excess thyroid cancer incidence in children/adolescents 0-4 and 5-18 years old at the time of accidentin 6 most contaminated regions of Ukraine Latency Incidence by age at exposure 1990-2000 Additional incidence per 10*5 PY Thyroid dose, Gy Thyroid dose, Gy Tronko 2008

  9. Effect of iodine deficiency and of stable iodine consumption Cardis 2005

  10. Major radiation epidemiology conclusions OR at 1 Gy~5.5 – 8.4 [ERR/Gy 1.9 – 19] Chernobyl (0-17 y.o.) Relative risk V.Ivanov 2010 Thyroid dose (Gy)

  11. II. Pathology Major histotypes of thyroid cancer in Ukraine and Belarus after Chernobyl PTC is the only type of thyroid carcinoma showing a significant increase after Chernobyl Belarus, based on 740 cases Prevalence, % FTC MTC PTC

  12. Chernobyl PTC subtypes 2478 cases from Ukraine S F Mix P Courtesy T.Bogdanova

  13. Age-related pathological features 2478 PTCs from Ukraine, age 0 – 18 years old at 26 April, 1986, diagnosed in 1990-2010 Children 67.6% Adolescents 52.4% Adults 34.0% Children 27.9% Adolescents 17.3% Adults 3.3% Courtesy T.Bogdanova

  14. Is radiation-induced PTC pathologically more aggressive than sporadic? Age-matched groups of radiogenic and sporadic PTC from Ukraine Courtesy T.Bogdanova

  15. Parameters associated with radiogenic PTC (born before Chernobyl) vs sporadic PTC (born after Chernobyl), logistic regression analysis in age-matched groups, final models Children <15 years old at surgery (N= 114 vs 111) Adolescents 15-<18 years old at surgery (N= 66 vs 97) Adults 18-23 years old at surgery (N= 59 vs 56) * Based on likelihood ratio test CI, confidence interval Courtesy T.Bogdanova

  16. Major pathological conclusions

  17. III. Clinical prognosis Mortality Tuttle 2011 Demidchik 2006 98.8% % Survival Belarus, 740 PTC Years follow-up Disease-specific mortality rate is low ~ 1% (15-20 years)

  18. Prognosis: recurrence Does radiation-induced PTC recur more readily than sporadic? Risk factors for disease-free survival in radiation-induced and sporadic PTC from Russia Cohort: 172 Chernobyl PTC with individual thyroid doses > 50 mGy 325 PTC with individual thyroid doses < 5 mGy • Matched by: • Sex • Age • Calendar time of treatment

  19. RI-PTC SP-PTC Proportional hazard model of disease-free survival in radiation-induced and sporadic PTC Rumyantsev 2011 HR=0.702 [0.465-1.090], P=0.118 (Logrank test) None of the 12 variables tested in the model interacted with radiation exposure attesting to the absence of risk factors for recurrence specific to radiation

  20. Effects of tumor capsule, nodal disease and treatment adequacy Risk factors 0 1 2 3

  21. Major clinical conclusions

  22. IV. Molecular characteristics MAP kinase pathway activation in PTC From A.Chiloeches, R.Marais Clin.Cancer Res., 2006

  23. (Table 12 Evolution of mutational events in time Chernobyl Japanese Hibakusha RET/PTC3 RET/PTC1 BRAF, RAS Williams 2008 Nakachi 2006 Prevalence Latency Major oncogenic events in PTC

  24. Detours 2005 12 Chernobyl and 8 Sporadic PTC 13 Adenomas 2400 genes Comparative gene expression studies Gene expression patterns in radiation-related and sporadic PTCs are similar on a global scale.

  25. Gene expression in 12 Chernobyl and 14 sporadic PTCs Detours 2007 Sporadic Chernobyl Based on 8,000 genes: • classifiers included from one to several thousand genes (median 256) • overall error rates in discrimination 12-27%

  26. Gene expression in 11 Chernobyl and 41 sporadic PTCs Port 2007 Among 29,000 genes: 646 were upregulated and 677 were downregulated (>5-fold difference) a 7-gene classifier

  27. Gene expression signature distinguishes normal tissues of sporadic and radiation-induced PTC unsupervised N-Spor N-Rad T-Spor T-Rad Dom et al, Sep 2012

  28. DNA copy number variation (CNV) Richter 2004 Kimmel 2006 Unger 2008 Stein 2010 • 30% PTCs display CNV • RET/PTC-positive and –negative cases could be distinguished • Besides carcinogenesis-related changes, CNV also depends • on radiation exposure • Prevalence of DNA gains is 2-4 times higher in Chernobyl PTCs • Recurrent gains are ~10 times more frequent in Chernobyl PTCs

  29. Gain of chromosome band 7q11 in Chernobyl PTC Hess 2011 Validation set: 16 Chernobyl (6/16=37.5%) 12 Sporadic (0/12=0%) Learning set: 33 Chernobyl (13/33=39.4%) 19 Sporadic (0/19=0%)

  30. Are there molecular signaturesof radiation-induced PTC? • Mutational studies: NONE of the oncogenes or tumor suppressors implicated in of PTC has proved a distinctive molecular signature of radiation-induced thyroid cancer • Gene expression and DNA copy alteration analyses are suggestive that molecular classifiers of radiation-induced PTC may exist • Validation in the larger independent series (matched for ethnicity/ age/ sex) of radiation-induced and sporadic cancers is urgently needed to understand if the establishment of a reliable radiation signature is achievable

  31. Molecular epidemiology studies Molecular epidemiology is an approach to the identification of genetic factors that influence health and disease Studies are conducted using advanced technologies to rapidly and cost-effectively analyze genetic differences between people with specific illnesses compared to healthy individuals The purpose is to explore the connection between specific genes, i.e. genotype, and phenotype, to facilitate the determination of genetic risk factors for the development of disease Linkage disequilibrium Gene 1 Marker 1 Mode of inheritance Gene 2 Linkage association Phenotype Gene 2 (complex) Individual environment Adapted from: Weiss and Terwilliger , 2000 Common environment Polygenic background

  32. Multi-stage design of an association study Genotype full set of SNPs in relatively small sample set at liberal P-value (GWAS) Genotype full or narrower set of SNPs in relatively small sample set to achieve more stringent P-value Validation: genotype narrow set of SNPs in extended sample set to increase stringent P-value * Reduces study cost but also decreases power to detect modest associations on meta

  33. Results of genetic association studies in sporadic thyroid cancer

  34. Areas of sampling of Chernobyl PTCs and controls P O L A N D 448 controls from the previous study Cases, approx 30 persons (total, 1098) Controls, approx 30 persons (total, 2309) Map from UNSCEAR 2008 Report Annex D 620 controls from the previous study

  35. Result: pooled analysis rs10759944 rs10759944 NRG1 : Weak association rs965513 rs965513 NKX2-1 or MBIP : NO association DIRC3 : NO association FOXE1 rs7850258 rs7850258 rs925489 rs925489 rs7024345 rs7024345 Genome-wide significance rs907580 rs907580 • 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 2122 Chromosomes FOXE1 locus at 9q22.33 is confirmed as the strongest NO association with 2q35 (DIRC3) and 14q13.3 (NKX2-1 orMBIP) Weak association with NRG1 at 8p12 SNPs associating with radiation-induced PTC also associate with sporadic PTC

  36. Final analysis Cases: 953(Bel) + 145(Ukr) = 1098 (1057 after QC) Controls: 1084(Bel) + 157(Ukr) + 448(Rus) + 620(Pol) = 2309 (2287 after QC)

  37. Risk factors for radiation-induced PTC SporadicRadiation-induced FOXE1 NRG1 • Genetic predisposition NO strong markers DIRC3 NKX2-1 or MBIP Predisposition to thyroid cancer Etiology-specific modifiers (?) weak (?) Radiation dose for the thyroid Age at exposure Iodine deficiency Sex(?)

  38. In conclusion Radiation-induced thyroid cancer… • Displays dose-response relationship; the highest risk is in the youngest children; no risk at doses below 100 mSv • Morphological aggressiveness declines with time and in the row children > adolescents > adults • May be morphologically more aggressive than sporadic • Is recommended to be treated and followed in the same way as sporadic thyroid cancers • May have molecular signature that combines gene expression pattern and DNA CNV • Has genetic risk markers common with sporadic

  39. Acknowledgements Nagasaki University Tatiana Rogounovitch Norisato Mitsutake Noboru Takamura Shunichi Yamashita (福島県立医科大学) Kyoto University Meiko Takahashi Takahisa Kawaguchi Ryo Yamada Fumihiko Matsuda MRRC RAMS Pavel Rumyantsev Anatoly Tsyb Alexander Abrosimov Valery Stepanenko BelMAPGE Valentina Drozd Larisa Danilova Maxim Lushchik Natallia Akulevich Yuri Demidchik CNG Simon Heath Mark Lathrop IEM Tatiana Bogdanova Mykola Tronko Vladimir Pushkarev Victor Shpak CNG

  40. Thank you for your attention!

More Related