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for subjects exposed at young age. Mechanistic risks models on the other hand provide risk estimates
based on the phenomenological description of cell-based processes. The biological plausibility of this class
of models is markedly improved by integrating molecular data on early carcinogenic events which are
related to cell proliferation and genomic instability. In this talk we present integration app-roaches for
such data into mechanistic risk models of PTC carcinogenesis. Deregulated MAPK is involved in the
majority of PTCs and active MAPK induces cell proliferation, which is a prerequisite for growth of a lesion.
Disturbed MAPK signaling in differentiated non-malignant thyroid tissue may indicate early molecular
changes on the pathway to cancer. From microarray expression data [1] on normal tissue (corresponding
to tumor tissue from UkrAm PTC patients) ten most informative genes have been identified and,
depending on their cellular location, a MAPK activation score has been defined. The score depends on
sex, age at exposure, age attained and radiation dose and is associated in the mechanistic model with
clonal expansion of cells carrying early molecular changes e.g. disturbed proliferation. The CLIP2 gene
represents a surrogate marker of genomic instability and de-regulated gene expression is preferentially
found in patients exposed at young age [2]. The role of CLIP2 for radiation-induced genomic instability is
explored with mechanistic models. Risk predictions from standard descriptive models and from
mechanistic models based on molecular data are compared for the UkrAm cohort.
1. Abend M, Pfeiffer RM, Ruf C, Hatch M, Bogdanova TI, et al. (2012) Iodine-131 dose dependent gene
expression in thyroid cancers and corresponding normal tissues following the Chernobyl accident. PLoS
One 7: e39103. 2. Hess J, Thomas G, Braselmann H, Bauer V, Bogdanova T, et al. (2011) Gain of chromo-
some band 7q11 in papillary thyroid carcinomas of young patients is associated with exposure to low-
dose irradiation. Proc Natl Acad Sci U S A 108: 9595-9600.
(S3004) Thyroid Cancer Risk Following Adult Radiation Exposure. Kiyohiko Mabuchi; Alina Brenner;
Maureen Hatch; Mark Little; Steve Simon; and Martha Linet, National Cancer Institute, Bethesda, MD
A large number of adults are exposed to radiation from medical, occupation and environmental
sources. The Fukushima Daiichi nuclear power plant in 2011 reminded us the possibility that large groups
- including many adults - can be exposed to radioactive iodine and external radiation, and that it is
important to understand the effect of age at exposure on cancer risk over entire age spectrum in order to
develop effective radiation protection standards. While the juvenile thyroid gland is at especially high risk
for developing cancer after radiation exposure, data on thyroid cancer related to adult exposure have
been relatively limited until recently. Cancer incidence data, mostly ecological, from Chernobyl clean-up
workers and other nuclear workers have suggested elevated risk of thyroid cancer following low dose
adult exposure. Most recently, a case-control study of Chernobyl clean-up workers in Belarus, Russia and
Baltic countries conducted by the International Agency for Research on Cancer has shown a significant
radiation risk of thyroid cancer, which appears to be much higher than expected from other studies of
exposed populations. We are currently conducting a pilot study of thyroid cancer in Ukrainian clean-up
workers to address the question regarding the radiation risk following adult exposure. Reviewing the
available literature on adult populations exposed to low and moderate doses from various sources of
radiation, one cannot discount, though not firmly establish, the elevation in risk of thyroid cancer, and
this underscores the need for further research.
100 | P a g e
based on the phenomenological description of cell-based processes. The biological plausibility of this class
of models is markedly improved by integrating molecular data on early carcinogenic events which are
related to cell proliferation and genomic instability. In this talk we present integration app-roaches for
such data into mechanistic risk models of PTC carcinogenesis. Deregulated MAPK is involved in the
majority of PTCs and active MAPK induces cell proliferation, which is a prerequisite for growth of a lesion.
Disturbed MAPK signaling in differentiated non-malignant thyroid tissue may indicate early molecular
changes on the pathway to cancer. From microarray expression data [1] on normal tissue (corresponding
to tumor tissue from UkrAm PTC patients) ten most informative genes have been identified and,
depending on their cellular location, a MAPK activation score has been defined. The score depends on
sex, age at exposure, age attained and radiation dose and is associated in the mechanistic model with
clonal expansion of cells carrying early molecular changes e.g. disturbed proliferation. The CLIP2 gene
represents a surrogate marker of genomic instability and de-regulated gene expression is preferentially
found in patients exposed at young age [2]. The role of CLIP2 for radiation-induced genomic instability is
explored with mechanistic models. Risk predictions from standard descriptive models and from
mechanistic models based on molecular data are compared for the UkrAm cohort.
1. Abend M, Pfeiffer RM, Ruf C, Hatch M, Bogdanova TI, et al. (2012) Iodine-131 dose dependent gene
expression in thyroid cancers and corresponding normal tissues following the Chernobyl accident. PLoS
One 7: e39103. 2. Hess J, Thomas G, Braselmann H, Bauer V, Bogdanova T, et al. (2011) Gain of chromo-
some band 7q11 in papillary thyroid carcinomas of young patients is associated with exposure to low-
dose irradiation. Proc Natl Acad Sci U S A 108: 9595-9600.
(S3004) Thyroid Cancer Risk Following Adult Radiation Exposure. Kiyohiko Mabuchi; Alina Brenner;
Maureen Hatch; Mark Little; Steve Simon; and Martha Linet, National Cancer Institute, Bethesda, MD
A large number of adults are exposed to radiation from medical, occupation and environmental
sources. The Fukushima Daiichi nuclear power plant in 2011 reminded us the possibility that large groups
- including many adults - can be exposed to radioactive iodine and external radiation, and that it is
important to understand the effect of age at exposure on cancer risk over entire age spectrum in order to
develop effective radiation protection standards. While the juvenile thyroid gland is at especially high risk
for developing cancer after radiation exposure, data on thyroid cancer related to adult exposure have
been relatively limited until recently. Cancer incidence data, mostly ecological, from Chernobyl clean-up
workers and other nuclear workers have suggested elevated risk of thyroid cancer following low dose
adult exposure. Most recently, a case-control study of Chernobyl clean-up workers in Belarus, Russia and
Baltic countries conducted by the International Agency for Research on Cancer has shown a significant
radiation risk of thyroid cancer, which appears to be much higher than expected from other studies of
exposed populations. We are currently conducting a pilot study of thyroid cancer in Ukrainian clean-up
workers to address the question regarding the radiation risk following adult exposure. Reviewing the
available literature on adult populations exposed to low and moderate doses from various sources of
radiation, one cannot discount, though not firmly establish, the elevation in risk of thyroid cancer, and
this underscores the need for further research.
100 | P a g e
