Institute of Endocrinology and Metabolism,
Kyiv, Ukraine
Tronko M.D.
FUNDAMENTAL AND APPLIED ASPECTS OF THE STUDY OF THYROID CANCER IN CHILDREN AND ADOLESCENTS IN UKRAINE
(30 years of surveillance) �
18 April 2016, Kyiv, Ukraine
Comparison of radioactive iodine I131 fallout from nuclear reactors
Episode | I131 fallout (Curie) |
Accident at Three Mile Island Nuclear Power Station, U.S.A (1979) | |
Accident at the reactor “Windscale”, UK (1957) | 20 000 |
Technological fallout from a reactor in the process of plutonium production at the enterprise in Hanford, Washington, U.S.A. | 690 000 |
Accident at Chernobyl Nuclear Power Station, Ukraine (1986)* | |
Accident at Fukushima Nuclear Power Station, Japan (2011)** | |
* In addition, fallouts of short-lived iodine and tellurium isotopes are estimated to be equal to 100,000,000 Curie (UNSCEAR 2008).
** Report of Japanese Government to IAEA Ministerial Conference on Nuclear Safety - Accident at TEPCO's Fukushima Nuclear Power Stations, 7 June 2011
15-20
40 000 000 – 50 000 000
4 000 000 – 5 000 000
Cumulative fallout of I131 in the territory of Ukraine as a result of the Chernobyl accident (April 26th – May 7th, 1986)
Likhtarev et al., “Radiation and risk", 2005
Cumulative I-131 fallout on the soil (MBq/m2)
0.16 mean regional values
of I131 fallout (kBq/m2)
Rayon average thyroid dose for children aged 0-18 at the time of the Chernobyl accident
UNSCEAR, 2008, Annex D.
Main components of Clinical-Morphological Registry (CMR)
Personal
records
Clinical data
Demography
Pathology
Dosimetry
Cooperation between CMR and other Registries
Clinical-Morphological Register,
IEM, Kiev
National Cancer Registry of Ukraine,
National Cancer Institute, Ukraine, Kiev
TherDep,
IEM, Kiev
Chernobyl Tissue Bank
Current number of thyroid cancer cases in CMR (1986 – 2014)
Population groups | Thyroid cancer cases | ||
Male | Female | Both | |
0-14 years old at the time of the accident | 1510 | 6496 | 8006 |
15-18 years old at the time of the accident | 399 | 2002 | 2401 |
Exposed in utero | 52 | 150 | 202 |
Born in 1987 and later | 270 | 1016 | 1286 |
Total | 2231 | 9664 | 11895 |
Ukrainian-American Thyroid Project
UkrAm cohort thyroid study – a classical prospective cohort study of radiation risk of thyroid cancer and other thyroid pathology in Ukrainian exposed as children and adolescent due to Chernobyl accident and having direct thyroid activity measurements in May-June 1986.
Distribution of selected and examined cohort by dose group
Dose group A
7542 (57.0%)
Dose group B
3457 (26.1%)
Dose group C
2244 (16.9%)
Number of cohort members examined
13243
Total number of records selected from dose file
34092
Dose group A D<0,3Gy
Low dose
15541(45.6%)
Dose group B 0,3<D<1,0Gy
Middle dose 8476(24.9%)
Dose group C
D>1,0Gy
High dose
10075 (29.6%)
Residence of cohort members in 1986
Number of cohort members
that underwent different screening rounds
1998-2000 2001-2003 2003-2005 2005-2007 2012-2015
Number of thyroid cancer cases according a place of residence in 1986
48
103
28
Histological types of thyroid carcinomas (179 cases)
Cumulative incidence of thyroid cancer cases
detected during 1st - 4th screening cycles
Cumulative incidence per 1000 subjects
Number of cases
Cumulative incidence of thyroid cancer cases
detected during nodular project (2009-2011)
and 5th screening cycle (2012-2015)
Cumulative incidence per 1000 subjects
Number of cases
UkrAm: estimates of thyroid cancer risk
Prevalence: cases diagnosed in 1998-2000
Tronko M.D., Howe G.R., Bogdanova T.I. et al. JNCI, Vol. 98, 2006
Dose-response prevalence of thyroid cancers detected during first screening cycle (1998-2000)
UkrAm: estimates of thyroid cancer risk
Brenner A.V., Tronko M.D., Hatch М., Bogdanova T.I. et al. EHP, March 2011, doi: 10.1289/ehp.1002674
I-131 Dose-Response for Incident Thyroid Cancers in Ukraine Related to the Chernobyl Accident
Incidence: cases diagnosed in 2001-2008
The ERR per Gy varied significantly by oblast of residence, but not by time since exposure. I-131-related thyroid cancer risks persisted for two decades following exposure.
Ukrainian-American in Utero Study:
- 1,498 from contaminated areas (individual thyroid dose ranged from 0-3,23 Gy)
- 1,089 from no/low-contaminated areas (individual thyroid dose ranged from 0-0,37 Gy)
(Hatch et al., JCEM, 2009; Likhtarev et al., Health Phys, 2011)
Summary of UkrAm in utero study
Based on 7 cases detected Risk of thyroid cancer from in utero exposure to I-131: (EOR/Gy=11.7 (95%CI: NE-1,982), P=0.12).
No clear evidence that the fetal thyroid is more sensitive to the carcinogenic effects of I-131 than that of the young child.
(Hatch et al., JCEM, 2008)
THE JOINT UKRAM THYROID COHORT
IN UTERO THYROID COHORT,
2600 subjects
prenatally exposure,
1st screening cycle 2003-2006
MAIN THYROID COHORT,
13200 subjects
aged < 18 at exposure,
1st-4th screening cycles 1998-2008
JOINT UKRAM THYROID COHORT,
15800 subjects
since 2009
Strengths of UkrAm Thyroid Study
Uniform screening using standardized procedures
Five cycles of clinical examinations with high retention rate in period 1998-2015
Good compliance with FNA and thyroid surgery
Individual questionnaire- and measurement- based thyroid doses
Wide range of individual doses (0.00035 - 42.0 Gy )
Advanced statistical models for accounting dose uncertainties
Detailed pathological analysis of the cases revealed.
Additional confirmation of diagnoses of International Pathology Panel (CTB)
Evaluation of iodine status
Evaluation of the scientific results and the research potential of the UkrAm by international experts
NCRP Report No. 159, Risk to the Thyroid from Ionizing Radiation, Bethesda (MD), 2008
UNSCEAR 2008 Report: "Sources and effects of ionizing radiation".
Volume II. Annex D - Health effects due to radiation from the Chernobyl accident
The Expert Group recommends to include
Children at exposure cohort ( UkrAm cohort, about 15,800)
into ‘Chernobyl Life Span Cohorts’
EC Project ARCH (Agenda for Research on Chernobyl Health (http://arch.iarc.fr/)) Williams et al., J Radiol Prot, 2011
Evolution of views and modern concepts
MOLECULAR BIOLOGY OF RADIATION-INDUCED THYROID CANCER
Involvement of mutations in three sites of gene RET, which activate Ras-Raf-MAP signal pathway [by Fagin J.A., 2004].
Grb7, 10
1062
РІ3-K
RET/PTC
905
1015
PLC
RAS
PKC
B-RAF
Proliferation
MEK
ERK
SOS
Grb2
Shc
Santoro M, Thomas GA, Vecchio G, Williams GH, Fusco A, Chiapetta G, Pozcharskaya V, Bogdanova TI, Demitchik EP, Cherstvoy ED, Voscoboinik L, Tronko ND, Carss A, Bunnell H., Tonnachera M, Parma J, Dumont JE, Keller G, Hofler H, Williams ED. Gene rearrangement and Chernobyl related thyroid cancer. British J Cancer. 2000; 82(2): 315-322.
| Radiation-induced PTC (n=45) |
RET/PTC1 | 7 (16%) |
RET/PTC3 | 12 (27%) |
RET/PTC1&3 | 1 (2%) |
Total: | 20 (44%) |
SF – solid-follicular structure
Pap – papillary structure
Expression of oncogenes RET/РТС
in papillary thyroid cancer in patients
from different age’s groups
1 group: 13 ± 1�2 group : 25 ± 1�3 group : 38 ± 1�
%
%
%
%
%
R2=0,16
R2=0,98
R2=0,99
*
**
*
*
Age
Mutation BRAFV600E
Romei C, Voskoboynyk L, Ciampi R, Bogdanova T, Elisei R, Tronko M, Pinchera A.
Gene alterations in post-Chernobyl benign and malignant thyroid tumors from Ukraine. 5th ETA CRN Meeting, Naples, Italy, September 1st. – 2006.
PTC | 6/25*(24.0%) |
FA | 0/24(0%) |
Mutation
BRAF V600Е
BRAF
wild type
� Genomic characterization of Chernobyl thyroid cancers �(NCI, IEM, CTB: in process)
500 PTC cases:
All UkrAm cohort PTC cases;
PTC cases from Chernigov, Kiev, Zhitomir regions, and Kiev-city (born before and after Chernobyl)
Paraffin embedded blocks
Frozen tissue samples
EDTA blood samples
Tumor – 1 block per case
Normal – 1 block per case
Mts - 1 block per case
Tumor – 1 sample per case
Normal – 1 sample per case
Mts - 1 sample per case
EDTA samples - 5 ml per case
Aims of Project: Comprehensive genomic characterization of
radiation-related thyroid cancer in the Ukraine
The key trends of further studies
Study of the time pattern of risk and effect of modifying factors in the period 13-29 years after exposure
New models of taking into account individual dose estimate uncertainties in the dose-response analysis
Molecular-biological and genetic studies based on Project materials
The pooled analysis of Belarus-American and Ukrainian-American data
Cooperation of Institute of Endocrinology
with international organizations and leading research institutions�
Institute of Endocrinology
UNICEF
WHO
USA:
National Cancer Institute, Columbia and California Universities, CDC, Atlanta
Great Britain :
Imperial College (London),
Wales University,
Cambridge University
Belgium:
Free University of Brussels
Japan:
Nagasaki Medical University, Sasakawa Foundation
Italy:
Napoli University, Milano University, Pisa University
France:
University of Reims
Canada:
Toronto University
Germany:
Helmholtz Zentrum München, Neuherberg;
University of Wuerzburg; Marburg University;
Berlin Humboldt University
European Union
THANK YOU FOR YOUR ATTENTION!