EDP Sciences logo
Subscriber Authentication Point
Search
Menu
Home All issues Volume 53 / No 1 (January-March 2018) Radioprotection, 53 1 (2018) 69-71 Full HTML
Free Access
This article is a note for:
[https://doi.org/10.1051/radiopro/2018005]

Issue
Radioprotection
Volume 53, Number 1, January-March 2018
Page(s) 69 - 71
DOI https://doi.org/10.1051/radiopro/2018004
Published online 07 March 2018

Comment on: Radioprotection 2018, 53(1), 67-68

In response

First, we would like to thank the authors of the Letter for their comments on our article. This response gives us the opportunity to further explain our points and to reinforce the impact of our review (Colin et al., 2017). The authors basically raise four points to which we respond.

1 Comparison between DNA damage caused by endogenous causes and DNA damage caused by medical radiological exposure

The statement that “DNA damage due to endogenous causes” are more numerous “than the DNA damage caused by low levels of radiation such as from diagnostic X-ray exposures” is questionable because the authors compared the effect of natural radiation background with that of acute doses. In fact, they omitted the impact of the dose rate. In addition, they did not consider the DNA damage repair as a function of time in their comparison. They only took into account the absolute numerical values without integrating them on a same period of time. Indeed, X-ray exposure for a mammographic view is delivered in less than 5 s while natural radiation background is delivered continuously. Hence, we proposed two examples of comparison by considering induced DNA double strand breaks (DSBs) and effective dose:

  • it is generally considered that each human cell is subjected to about 8 induced DSBs per day, which represents the major DNA damage induced by endogenous causes (Lieber and Karanjawala, 2004). It is well documented that a dose of 1 Gy of X-rays induces 40 DSBs per human diploid cell independently of dose range and cellular radiosensitivity (Foray et al., 2016). A mean glandular dose of 2 mGy per mammographic view corresponds therefore to the induction of 0.08 DSBs per cell, but induced in 5 s. In comparison, endogenous causes induce 0.00046 DSBs, i.e., 172 times less in the same period of time;

  • natural radiation background is expressed as effective dose (e.g., 2.4 mSv y-1 is the average natural radiation background in Europe). In the case of mammography, a mean glandular dose of 2 mGy for each breast corresponds to an effective dose of 2 × 0.12 mSv = 0.24 mSv (taking into account the weighting factor for the breast WT = 0.12). But, again, this effective dose is delivered in 5 s while natural radiation background effective dose is 0.315 nSv in the same period of time. In this case, the ratio is about 762.

Hence, these two methods of calculations contradict the opinion of the authors in their letter.

2 Boosting of immune system and DNA repair

The authors of the letter argued that “the increased damage from low-dose radiation would boost defenses such as antioxidants and DNA repair enzymes… and the immune system… and so would reduce DNA damage from endogenous causes… and eliminate the cancer cells more effectively, reducing the cancer risk”. This statement does not hold if we take in consideration several issues from epidemiology, radiation biology and immunology.

Epidemiological data show that ionizing radiations constitute a risk of cancer which increases with dose (Preston et al., 2002; Wakeford 2004). These data establish an increase of the breast cancer risk linked to the increase of cumulated doses (Ronckers et al., 2005), especially at young age at exposure (Hoffman et al., 1989; Miller et al., 1989; Howe and McLaughlin, 1996; Doody et al., 2000). This is the case even for very low cumulated doses in BRCA mutation carriers (Pijpe et al., 2012). Furthermore, even if we introduce the notion of dose threshold below which the immune system, anti-oxidants, and DNA repair enzyme contribution are significant to reduce cancer incidence, it would include the natural radiation background. However, there is no significant difference between cancer incidence in the regions of low natural radiation background (e.g., Japan) and of high natural radiation background (e.g., Ramsar, Iran) while the ratio between the corresponding natural radiation backgrounds is about 100.

Radiation biology data certainly show that DNA repair enzymes are mobilized after exposure to ionizing radiation above a significant dose to trigger signalization of DNA damage. However, this does not last very long, indeed a few days at most. Therefore, a mammography examination every two years cannot produce a significant long lasting level of intracellular defenses able to confer radioresistance to protect from breast cancer. Furthermore, one cannot even imagine that an eventual boosting of DNA repair enzymes would improve the poor functioning of genetically altered BRCA proteins in these mutated patients.

The hypothesis that the immune system would better eliminate irradiated precancerous cells than non-precancerous cells generally originates from a biased interpretation of the hypersensitivity to low doses (HRS) phenomenon (Tubiana, 2005). However, it was clearly showed that: i) the HRS phenomenon is limited to 25% excess of cell death and would therefore not concern all the irradiated cells (Thomas et al., 2013); ii) the HRS phenomenon is also observed in primary fibroblasts and therefore not specifically in precancerous cells (Slonina et al., 2007); iii) the HRS phenomenon is not limited to cell death and can be associated with excess of cell mutations, in complete disagreement with the hypotheses of the authors of the letter (Xue et al., 2009).

Finally, there is no evidence that ionizing radiation boosts the immune system but there is evidence that ionizing radiation induces ageing of immunocompetent cells (UNSCEAR, 2006).

3 Consistency of epidemiological data

It must be stressed that, despite of all the biases due to the variety of the diagnostic procedures (Tab. 3 of our review), the great majority of epidemiological studies show the same trend, suggesting a radiation-induced cancer risk linked to the BRCA mutational status, whatever the design of the epidemiological study. Besides, in our review, there is only one study taking into account the cumulated doses of all the radiological breast exposures (Pijpe et al., 2012) and this study is in agreement with the majority of the others (Fig. 1 of our review). Notably, this is a major point for clinical practice: avoiding thoracic computed tomography in BRCA (or P53) mutation carrier should be considered a must for clinicians. Therefore, the argument of the authors of the letter concerning the inconsistency and the weakness of the epidemiological data gathered in our review does not stand.

4 Radiation-induced mutations and radiation-induced cancer risk

The authors present the following syllogism: “The number of natural mutations is significantly larger than those created by low-dose ionizing radiation. If low-dose radiation is a hazard, one would expect that the natural mutations would propagate cancer at a rate larger than observed. Since this does not occur, the DNA repair mechanisms and human immune system must function efficiently to remove both naturally occurring abnormalities and those caused by low-doses of ionizing radiation.” The first sentence is not in agreement with the very documented observation that mutation frequency increases with dose and, as stated above, omits the dose rate effect that refers to the point 1 of our reply. The incidence of heterozygous mutations of genes of DNA damage signaling and repair pathways that all confer cancer-proneness may represent together 5–20% of the whole population, which is not negligible. Interestingly, all these gene mutations are not necessarily associated with immunodeficiency. Finally, if DNA repair mechanisms and human immune system must function efficiently to remove both naturally occurring abnormalities and those caused by low-doses of ionizing radiation, how to explain that 5–20% of the whole female population is at high increased risk of breast cancer?

References

  • Colin C, Foray N, Di Leo G, Sardanelli F. 2017. Radiation induced breast cancer risk in BRCA mutation carriers from low-dose radiological exposures: a systematic review, Radioprotection 52: 231–240. [CrossRef] [EDP Sciences] [Google Scholar]
  • Doody MM, Lonstein JE, Stovall M, Hacker DG, Luckyanov N, Land CE. 2000. Breast cancer mortality after diagnostic radiography: findings from the U.S. Scoliosis Cohort Study, Spine (Phila Pa 1976) 25: 2052–2063. [CrossRef] [PubMed] [Google Scholar]
  • Foray N, Bourguignon M, Hamada N. 2016. Individual response to ionizing radiation, Mutat. Res. Rev. 770: 369–386. [CrossRef] [PubMed] [Google Scholar]
  • Hoffman DA, Lonstein JE, Morin MM, Visscher W, Harris BS, 3rd, Boice JD, Jr. 1989. Breast cancer in women with scoliosis exposed to multiple diagnostic X rays, J. Natl. Cancer. Inst. 81: 1307–1312. [Google Scholar]
  • Howe GR, McLaughlin J. 1996. Breast cancer mortality between 1950 and 1987 after exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian fluoroscopy cohort study and a comparison with breast cancer mortality in the atomic bomb survivors study, Radiat. Res. 145: 694–707. [CrossRef] [PubMed] [Google Scholar]
  • Lieber MR, Karanjawala ZE. 2004. Ageing, repetitive genomes and DNA damage, Nature Rev. Mol. Cell. Biol. 5: 69–75. [CrossRef] [Google Scholar]
  • Miller AB et al. 1989. Mortality from breast cancer after irradiation during fluoroscopic examinations in patients being treated for tuberculosis, N. Engl. J. Med. 321: 1285–1289. [CrossRef] [PubMed] [Google Scholar]
  • Pijpe A et al. 2012. Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK), BMJ 345: e5660. [Google Scholar]
  • Preston DL, Mattsson A, Holmberg E, Shore R, Hildreth NG, Boice JD, Jr. 2002. Radiation effects on breast cancer risk: a pooled analysis of eight cohorts, Radiat. Res. 158: 220–235. [CrossRef] [PubMed] [Google Scholar]
  • Ronckers CM, Erdmann CA, Land CE. 2005. Radiation and breast cancer: a review of current evidence, Breast Cancer Res. 7: 21–32. [CrossRef] [PubMed] [Google Scholar]
  • Slonina D et al. 2007 Low-dose radiation response of primary keratinocytes and fibroblasts from patients with cervix cancer, Radiat. Res. 167: 251–259. [CrossRef] [PubMed] [Google Scholar]
  • Thomas C, Martin J, Devic C, Bräuer-Krisch E, Diserbo M, Thariat J, Foray N. 2013. Impact of dose-rate on the low-dose hyper-radiosensitivity and induced radioresistance (HRS/IRR) response, Int. J. Radiat. Biol. 89(10): 813–822. [CrossRef] [PubMed] [Google Scholar]
  • Tubiana M. 2005. Dose-effect relationship and estimation of the carcinogenic effects of low doses of ionizing radiation: The joint report of the Académie des sciences (Paris) and of the Académie nationale de médecine, Int. J. Radiat. Oncol. Biol. Phys. 63: 317–319. [CrossRef] [PubMed] [Google Scholar]
  • UNSCEAR report. 2006. Effects of ionizing radiation. United Nations Scientific Committee on the effects of Atomic Radiation. Volume II. Scientific Annex D. Effects of ionizing radiation on the immune system, pp. 85–195. [Google Scholar]
  • Wakeford R. 2004. The cancer epidemiology of radiation, Oncogene 23: 6404–6428. [CrossRef] [PubMed] [Google Scholar]
  • Xue L et al. 2009. Atm-dependent hyper-radiosensitivity in mammalian cells irradiated by heavy ions, Int. J. Radiat. Oncol. Biol. Phys. 75: 235–243. [CrossRef] [PubMed] [Google Scholar]

Cite this article as: Colin C, Foray N, Di Leo G, Sardanelli F. 2018. Reply to the Comments on “Radiation induced breast cancer risk in BRCA mutation carriers from low-dose radiological exposures: a systematic review”. Radioprotection 53(1): 69–71


© EDP Sciences 2018

Current usage metrics show cumulative count of Article Views (full-text article views including HTML views, PDF and ePub downloads, according to the available data) and Abstracts Views on Vision4Press platform.

Data correspond to usage on the plateform after 2015. The current usage metrics is available 48-96 hours after online publication and is updated daily on week days.

Initial download of the metrics may take a while.