- Email: [email protected]
Now Is the Time to Consider Personalized Effective Dose
Accepted Manuscript Now is the time to consider personalized effective dose Hisanori Fukunaga, MD, Akinari Yokoya, PhD, Yasuyuki Taki, MD, PhD PII:
S0360-3016(16)30323-6
DOI:
10.1016/j.ijrobp.2016.06.012
Reference:
ROB 23622
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 2 June 2016 Accepted Date: 9 June 2016
Please cite this article as: Fukunaga H, Yokoya A, Taki Y, Now is the time to consider personalized effective dose, International Journal of Radiation Oncology • Biology • Physics (2016), doi: 10.1016/ j.ijrobp.2016.06.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Now is the time to consider personalized effective dose
1
RI PT
Hisanori Fukunaga, MD1,2, Akinari Yokoya, PhD3, and Yasuyuki Taki, MD, PhD2
Soma General Hospital, Fukushima, Japan, 2Department of Nuclear Medicine and
Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai,
SC
Japan, and 3Tokai Quantum Beam Science Center, Quantum Beam Science Research
Directorate, National Institutes for Quantum and Radiological Science and Technology,
M AN U
Ibaraki, Japan.
Corresponding: Hisanori Fukunaga, MD, Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, 4-1
TE D
Seiryomachi, Aoba-ku, Sendai 980-8575, JAPAN. Tel: +81-22-717-8559; Fax: +81-22-717-8660; E-mail: [email protected]
EP
Short title: Personalized effective dose
AC C
Conflict of interest: None
Acknowledgments: None
ACCEPTED MANUSCRIPT
Individual variation in radiation sensitivity has been investigated for innovative radiation protection and therapy. For instance, some single nucleotide polymorphisms
RI PT
(SNPs) have been reported as potential biomarkers for predicting the development of
radiation pneumonitis (RP), one of the adverse effects of radiation therapy (1-5). Such
SC
SNPs in DNA repair-related, cell signaling-related, and inflammation-related genes
M AN U
were statistically proven to be associated with RP, suggesting direct or indirect involvement in radiation sensitivity. As of May 31, 2016, we have estimated the SNPs frequency among the Japanese general population using iJGVD (https://ijgvd.megabank.tohoku.ac.jp/), an integrative Japanese genome variation
TE D
database based on whole genome sequencing of 1,070 Japanese individuals (6,7), to investigate the individual variation in radiation sensitivity and potential low-dose
EP
radiation-induced health risk in Fukushima after the 2011 nuclear power plant accident.
AC C
As shown in Table 1, with the assumption of the Hardy-Weinberg equilibrium, a large number of individuals have the SNPs associated with the risk of developing RP, indicating that the genetic diversity of radiation sensitivity is greater than expected. If the variation of radiation sensitivity is in fact greater than what was estimated, is the conventional concept of effective dose suitable for predicting individual radiation-induced health risks?
ACCEPTED MANUSCRIPT
Applying genetic variations and genomics approaches to the medical field is becoming more common nowadays, and precision medicine, a new conceptual model
RI PT
from personalized medicine, is widely accepted. However, in the matter of
radiation-induced health risks, the concept of effective dose is currently being used,
SC
although it doesn’t take the genetic diversity of radiation sensitivity into consideration.
M AN U
The effective dose takes into account only the type of radiation and the characteristics of each organ or tissue being irradiated. Thus, it doesn’t seem to be suited to estimate the individual radiation-induced health risks for residents, including young children, with greater than average radiation sensitivity because of their genetic background. In view
TE D
of this situation, we would like to suggest a simple concept, personalized effective dose (EP), which can be calculated from the effective dose to the entire organism (E) and
ܧ = ܹ × ܧௌ
AC C
EP
weighting factors for radiation sensitivity (WS):
The personalized effective dose will be essential for providing the
next-generation radiation protection and therapy as well as for estimating the personal radiation-induced health risks for individuals suffering from the Fukushima nuclear crisis (8). Although public health administrators and medical professionals should continue to make concerted efforts to minimize the radiation-induced risks for citizens,
ACCEPTED MANUSCRIPT
especially children, there appears to have been too little consideration of their genetic background and how it might affect their radiation sensitivity. Also, radiation biologists
RI PT
and oncologists should work to identify the rigorous predictors of radiation sensitivity
AC C
EP
TE D
M AN U
SC
and prepare the weighting factors.
ACCEPTED MANUSCRIPT
References 1. Zhang L, Yang M, Bi N, et al. ATM polymorphisms are associated with risk of
RI PT
radiation-induced pneumonitis. Int J Radiat Oncol Biol Phys 2010;77:1402-1407.
2. Yin M, Liao Z, Liu Z, et al. Genetic variants of the nonhomologus end joining LIG4
M AN U
definitive radiotherapy. Cancer 2012;118:528-535.
SC
and severe radiation pneumonitis in nonsmall cell lung cancer patients treated with
3. Yin M, Liao Z, Liu Z, et al. Functional polymorphisms of base excision repair genes XRCC1 and APEX1 predict risk of radiation pneumonitis in patients with non-small
2011;81:e67-e73.
TE D
cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys
4. Tang Y, Liu B, Li J, et al. Genetic variants in PI3K/AKT pathway are associated with
EP
severe radiation pneumonitis in lung cancer patients treated with radiation therapy.
AC C
Cancer Med 2016;5:24-32.
5. Edvardsen H1, Landmark-Høyvik H, Reinertsen KV, et al. SNP in TXNRD2 associated with radiation-induced fibrosis: a study of genetic variation in reactive oxygen species metabolism and signaling. Int J Radiat Oncol Biol Phys 2013;86:791-799. 6 Yamaguchi-Kabata Y, Nariai N, Kawai Y, et al. iJGVD: an integrative Japanese
ACCEPTED MANUSCRIPT
genome variation database based on whole-genome sequencing. Hum Genome Var 2015;2:15050.
RI PT
7 Nagasaki M, Yasuda J, Katsuoka F, et al. Rare variant discovery by deep
whole-genome sequencing of 1,070 Japanese individuals. Nat Commun 2015;6: 8018.
SC
8 Fukunaga H, Yokoya A. Low-dose radiation risk and individual variations in
AC C
EP
TE D
M AN U
radiation sensitivity in Fukushima. J Radiat Res 2016;57:98-100.
ACCEPTED MANUSCRIPT
Table 1 Gene polymorphisms on the risk of radiation pneumonitis and iJGVD variation frequency
G C G T A A
Reference allele frequency 0.5516 0.5776 0.8776 0.5832 0.574 0.5144
Alternative allele A T A G G G
Alternative allele frequency
Refs.
RI PT
rs189037 rs373759 rs1805388 rs1130409 rs11880261 rs1800469
Reference allele
0.4484 0.4224 0.1224 0.4168 0.426 0.4856
SC
ATM ATM LIG4 APEX1 AKT2 TGFβ1
SNP ID
M AN U
Gene
(1) (1) (2) (3) (4) (5)
Abbreviations: ATM = ataxia telangiectasia mutated; LIG4 = DNA ligase 4; APEX1 = apurinic /
AC C
EP
TE D
apyrimidinic endonuclease 1; AKT2 = Ak strain transforming 2; TGFβ1 = transforming growth factor-β1.
S0360-3016(16)30323-6
DOI:
10.1016/j.ijrobp.2016.06.012
Reference:
ROB 23622
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 2 June 2016 Accepted Date: 9 June 2016
Please cite this article as: Fukunaga H, Yokoya A, Taki Y, Now is the time to consider personalized effective dose, International Journal of Radiation Oncology • Biology • Physics (2016), doi: 10.1016/ j.ijrobp.2016.06.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Now is the time to consider personalized effective dose
1
RI PT
Hisanori Fukunaga, MD1,2, Akinari Yokoya, PhD3, and Yasuyuki Taki, MD, PhD2
Soma General Hospital, Fukushima, Japan, 2Department of Nuclear Medicine and
Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai,
SC
Japan, and 3Tokai Quantum Beam Science Center, Quantum Beam Science Research
Directorate, National Institutes for Quantum and Radiological Science and Technology,
M AN U
Ibaraki, Japan.
Corresponding: Hisanori Fukunaga, MD, Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, 4-1
TE D
Seiryomachi, Aoba-ku, Sendai 980-8575, JAPAN. Tel: +81-22-717-8559; Fax: +81-22-717-8660; E-mail: [email protected]
EP
Short title: Personalized effective dose
AC C
Conflict of interest: None
Acknowledgments: None
ACCEPTED MANUSCRIPT
Individual variation in radiation sensitivity has been investigated for innovative radiation protection and therapy. For instance, some single nucleotide polymorphisms
RI PT
(SNPs) have been reported as potential biomarkers for predicting the development of
radiation pneumonitis (RP), one of the adverse effects of radiation therapy (1-5). Such
SC
SNPs in DNA repair-related, cell signaling-related, and inflammation-related genes
M AN U
were statistically proven to be associated with RP, suggesting direct or indirect involvement in radiation sensitivity. As of May 31, 2016, we have estimated the SNPs frequency among the Japanese general population using iJGVD (https://ijgvd.megabank.tohoku.ac.jp/), an integrative Japanese genome variation
TE D
database based on whole genome sequencing of 1,070 Japanese individuals (6,7), to investigate the individual variation in radiation sensitivity and potential low-dose
EP
radiation-induced health risk in Fukushima after the 2011 nuclear power plant accident.
AC C
As shown in Table 1, with the assumption of the Hardy-Weinberg equilibrium, a large number of individuals have the SNPs associated with the risk of developing RP, indicating that the genetic diversity of radiation sensitivity is greater than expected. If the variation of radiation sensitivity is in fact greater than what was estimated, is the conventional concept of effective dose suitable for predicting individual radiation-induced health risks?
ACCEPTED MANUSCRIPT
Applying genetic variations and genomics approaches to the medical field is becoming more common nowadays, and precision medicine, a new conceptual model
RI PT
from personalized medicine, is widely accepted. However, in the matter of
radiation-induced health risks, the concept of effective dose is currently being used,
SC
although it doesn’t take the genetic diversity of radiation sensitivity into consideration.
M AN U
The effective dose takes into account only the type of radiation and the characteristics of each organ or tissue being irradiated. Thus, it doesn’t seem to be suited to estimate the individual radiation-induced health risks for residents, including young children, with greater than average radiation sensitivity because of their genetic background. In view
TE D
of this situation, we would like to suggest a simple concept, personalized effective dose (EP), which can be calculated from the effective dose to the entire organism (E) and
ܧ = ܹ × ܧௌ
AC C
EP
weighting factors for radiation sensitivity (WS):
The personalized effective dose will be essential for providing the
next-generation radiation protection and therapy as well as for estimating the personal radiation-induced health risks for individuals suffering from the Fukushima nuclear crisis (8). Although public health administrators and medical professionals should continue to make concerted efforts to minimize the radiation-induced risks for citizens,
ACCEPTED MANUSCRIPT
especially children, there appears to have been too little consideration of their genetic background and how it might affect their radiation sensitivity. Also, radiation biologists
RI PT
and oncologists should work to identify the rigorous predictors of radiation sensitivity
AC C
EP
TE D
M AN U
SC
and prepare the weighting factors.
ACCEPTED MANUSCRIPT
References 1. Zhang L, Yang M, Bi N, et al. ATM polymorphisms are associated with risk of
RI PT
radiation-induced pneumonitis. Int J Radiat Oncol Biol Phys 2010;77:1402-1407.
2. Yin M, Liao Z, Liu Z, et al. Genetic variants of the nonhomologus end joining LIG4
M AN U
definitive radiotherapy. Cancer 2012;118:528-535.
SC
and severe radiation pneumonitis in nonsmall cell lung cancer patients treated with
3. Yin M, Liao Z, Liu Z, et al. Functional polymorphisms of base excision repair genes XRCC1 and APEX1 predict risk of radiation pneumonitis in patients with non-small
2011;81:e67-e73.
TE D
cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys
4. Tang Y, Liu B, Li J, et al. Genetic variants in PI3K/AKT pathway are associated with
EP
severe radiation pneumonitis in lung cancer patients treated with radiation therapy.
AC C
Cancer Med 2016;5:24-32.
5. Edvardsen H1, Landmark-Høyvik H, Reinertsen KV, et al. SNP in TXNRD2 associated with radiation-induced fibrosis: a study of genetic variation in reactive oxygen species metabolism and signaling. Int J Radiat Oncol Biol Phys 2013;86:791-799. 6 Yamaguchi-Kabata Y, Nariai N, Kawai Y, et al. iJGVD: an integrative Japanese
ACCEPTED MANUSCRIPT
genome variation database based on whole-genome sequencing. Hum Genome Var 2015;2:15050.
RI PT
7 Nagasaki M, Yasuda J, Katsuoka F, et al. Rare variant discovery by deep
whole-genome sequencing of 1,070 Japanese individuals. Nat Commun 2015;6: 8018.
SC
8 Fukunaga H, Yokoya A. Low-dose radiation risk and individual variations in
AC C
EP
TE D
M AN U
radiation sensitivity in Fukushima. J Radiat Res 2016;57:98-100.
ACCEPTED MANUSCRIPT
Table 1 Gene polymorphisms on the risk of radiation pneumonitis and iJGVD variation frequency
G C G T A A
Reference allele frequency 0.5516 0.5776 0.8776 0.5832 0.574 0.5144
Alternative allele A T A G G G
Alternative allele frequency
Refs.
RI PT
rs189037 rs373759 rs1805388 rs1130409 rs11880261 rs1800469
Reference allele
0.4484 0.4224 0.1224 0.4168 0.426 0.4856
SC
ATM ATM LIG4 APEX1 AKT2 TGFβ1
SNP ID
M AN U
Gene
(1) (1) (2) (3) (4) (5)
Abbreviations: ATM = ataxia telangiectasia mutated; LIG4 = DNA ligase 4; APEX1 = apurinic /
AC C
EP
TE D
apyrimidinic endonuclease 1; AKT2 = Ak strain transforming 2; TGFβ1 = transforming growth factor-β1.