Health Risks from Exposure to Low Levels of Ionizing Radiation BEIR VII Phase 2 (2006) / Chapter Skim
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3 Radiation-Induced Cancer: Mechanisms, Quantitative Experimental Studies and the Role of Genetic Factors
3 Radiation-Induced Cancer: Mechanisms, Quantitative Experimental Studies and the Role of Genetic Factors
Pages 65-90
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From page 65... ...
duced cancer that emerge from epidemiologic and experi Subsequently, experimental studies addressing the quantitamental investigations. tive relationship between radiation dose and cancer develop Based mainly on experimental studies, it is generally be ment are reviewed with particular regard to their consistency lieved that complex forms of DNA double-strand breaks are with proposed underlying mechanisms and the overall imthe most biologically important type of lesions induced by plications for cancer risk at low doses.
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From page 66... ...
malignant conversion, which represents the tumorigenic gene activation or intragenic fusion involving juxtaposition phase where the evolving clonal population of cells becomes of DNA sequences by specific chromosomal exchange; increasingly committed to malignant development; mutation Rabbitts 1994; Greaves and Wiemels 2003)
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From page 67... ...
In such cases, mutational loss of func- can arise early in lymphoma and leukemia. The relatively tion can lead to deficiency in DNA damage response and early spontaneous development of genomic instability via repair, repair or recombination, chromosomal segregation, specific mutation of caretaker genes is believed to be imporcell cycle control, and/or apoptotic response (Loeb 1991; tant for tumorigenesis in many tissues, but epigenetic gene Hartwell and others 1994; Fishel and Kolodner 1995; Kinzler silencing or activation events have also been characterized.
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From page 68... ...
A possible the studies cited above do not give consistent evidence that exception to this is that an excess of complex chromosomal TP53 is a primary target for ionizing radiation. events and microsatellite sequence instability was observed A cytogenetic-molecular data set is available on papillary in late-expressing myeloid leukemias arising in A-bomb surthyroid cancer (PTC)
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From page 69... ...
data on tumorigenesis could be explained by radiation-in- Studies with gene knockout mice are providing further duced loss of the whole chromosome (chr11) bearing wt evidence on the role of DNA damage response genes in deTrp53, with duplication of the copy bearing mTrp53 being termining the in vivo radiosensitivity of cells and tissue, tonecessary to regain cellular genetic balance (Bouffler and gether with the impact on growth or development and sponothers 1995)
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From page 70... ...
An obvious caveat to this conclusion is the degree to Chromatid Instability in Hematopoietic Cells which these limited mechanistic data provide support for broad judgments about radiation risk at low doses. For ex- Radiation-induced genomic instability in hematopoietic ample, the data cited on the tolerance of aneuploidy in the cells was first revealed by studies showing a persistent exbone marrow of irradiated Trp53-deficient mice can explain cess of chromatid-type aberrations in the progeny of mouse the high-frequency development of lymphoma but may not bone marrow cells irradiated in vitro with -particles and be wholly relevant to other tissues and/or other genetic set- subsequently grown in culture (Kadhim and others 1992)
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From page 71... ...
for stricted to BALB/c suggesting genetic associations with perinduced genomic instability in bone marrow cells in culture sistent genomic instability and mammary tumor susceptibil(Kadhim and others 1992) is somewhat inconsistent with the ity.
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From page 72... ...
. forms, telomeric repeats are also found in subtelomeric and In conclusion, although the position regarding radiationinterstitial chromosomal locations, and there is some evi- induced persistent genomic instability and its causal assodence that these loci may act as sites at which radiation- ciation with tumorigenesis is not well understood, a few speinduced and other forms of genomic damage are preferen- cific points can be made: tially resolved (Bouffler 1998)
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From page 73... ...
This conclusion is strengthened use of appropriate analytical methodology must be considwhen account is also taken of the uncertainties noted in ered. Second, biological factors involved in the pathogenChapter 2 regarding the biological basis and generality of esis of specific neoplasms must be considered with respect the expression of induced genomic instability in cultured to the applicability of the experimental model to carcinogenmammalian cells.
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From page 74... ...
. These results with a linear model over a wide range of doses and with should not be unexpected since the development of thymic linear, time-independent effects at low doses, low-dose fraclymphoma in mice following irradiation is an extremely tions, and low dose rates (Shellabarger and others 1980)
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From page 75... ...
is ~50 mGy) , ovarian tumors occur at very high the multiple high-dose fractions of radiation that are generfrequencies following relatively low doses of ionizing radia- ally required to induce skin tumors in mouse skin are acting tion (Ullrich and Storer 1979c)
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From page 76... ...
doses of radiation and for radiation delivered at low dose rates, such life shortening is due almost entirely to radiation induced cancer (Storer and others 1979, 1982; Carnes and Postirradiation Persistence of Initiated Cells others 2002, 2003)
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From page 77... ...
. With few exceptions, dose-response re- duced cancer in human populations derived from studies lationships derived from life-shortening data following following acute radiation exposures tend to overestimate rasingle acute radiation doses, fractionated exposures, and ter- diation risks at low doses and low dose rates.
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From page 78... ...
Since 1994 a number of further animal Since the ratio should be equally valid for estimating effects studies have reported evidence suggestive of some form of at low dose rates (the DREF) and for low single doses, the adaptive response in the development of certain tumors.
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From page 79... ...
demonstrated an excess of skin cancer in sun-exposed DNA, repair-deficient xeroderma pigmentosum (XP) patients (i.e., Autosomal Recessive Disorders there was likely to be a direct association between heritable The majority of human genetic diseases associated with DNA repair or damage response capacity and cancer devel DNA damage response and repair fall into this category.
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From page 80... ...
) DNA damage recognition Various 1 in 50,000 Heritable breast or ovarian cancer BRCA-1 Transcriptional regulation, Breast or ovarian cancer 1 in 1000 BRCA-2 DNA repair Breast cancer (also male)
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From page 81... ...
Given that, on average, spontaneous cancer in- Stated simply, germline deficiency in the recognition and/or cidence in the general population is around 30%, the infor- repair of induced DNA damage of specific forms is expected mation currently available is restricted largely to mutations to increase the abundance of genome-wide damage in the where the cancer in question is expressed at a high relative somatic cells of body tissues. This increased mutational load frequency in gene carriers (i.e., so-called high-penetrance will tend to increase cancer risk, albeit with differing demutations)
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From page 82... ...
More recent studies on tion between the Brca genes, Rad51, cell cycle perturbation, the possible radiosensitivity of cells from breast cancer-sus- and DNA damage response. ceptible BRCA1 and BRCA2 patients have also provided The most valuable animal genetic data on radiation tumconflicting evidence (Buchholz and others 2002; Trenz and origenesis have been developed from studies on mice others 2002; Powell and Kachnic 2003)
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From page 83... ...
. The vided by molecular analysis of tumors arising in irradiated principal message from this experimental work is that beTp53+/ , Apc+/ , and Ptch+/ mice and Tsc-2+/ rats; as pre cause of the strongly modifying effects of genetic backdicted, such analyses strongly suggest that radiation acts by ground, rodent homologues are unlikely to provide a quantiinactivating the wild-type tumor-suppressor gene copy in tatively reliable representation of radiation tumorigenesis in target somatic cells.
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From page 84... ...
In brief, there is evidence of an excess of radiotherapy sistent with other epidemiologic data on radiation tumori(RT) -related tumors in the human cancer-prone conditions genesis where high background cancer rates also tend to be heritable retinoblastoma, NBCCS, and LFS plus related con- accompanied by lower ERRs.
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From page 85... ...
However, not unexpectedly, an unrisk imposed by the given gene mutations; the risk of radio- derstanding of this issue is proving difficult to obtain. To a genic breast cancer in normal individuals was based on data large measure this is due to the likelihood that, individually, from Japanese atomic bomb survivors.
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From page 86... ...
. For good scientific reasons, some early claims on substan- Finally, in illustration of ongoing work, it is relevant to tial risks at low doses are not regarded as being well mention polymorphic associations between GSTP1 and chefounded (see ICRP 1998)
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From page 87... ...
. These studies have By contrast, another set of investigations has associated a the capacity to provide proof-of-principle evidence of the strain-specific functional polymorphism of the gene Prkdc impact of such common loci, together with their possible encoding DNA PKcs with induced genomic instability, DNA interactions and tissue specificity, as well as the classes of DSB repair deficiency, and susceptibility to radiation-ingenes and mechanisms involved.
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From page 88... ...
. From recent studies, it seems likely to a range of radiogenic tumors in a genetically heterogethat one such gene is ATM, which in the heterozygous form neous human population would tend to lead to a situation in can enhance the frequency of both genomic instability and which the balance between a certain set of tumor susceptibilductal dysplasia of the breast of irradiated mice (Weil and ity (S)
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From page 89... ...
How ever, since the induction or development of these two cancer Mechanisms of Radiation Tumorigenesis types is believed to proceed via atypical mechanisms involv A critical conclusion on mechanisms of radiation tumori- ing cell killing, it was judged that the threshold-like regenesis is that the data reviewed greatly strengthen the view sponses observed should not be generalized. that there are intimate links between the dose-dependent in- Radiation-induced life shortening in mice is largely a reduction of DNA damage in cells, the appearance of gene or flection of cancer mortality, and the data reviewed generally chromosomal mutations through DNA damage misrepair, support the concept of a linear dose-response at low doses and the development of cancer.
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From page 90... ...
A preliminary conclusion is that common polymortical issue associated with these strongly expressing cancer phisms of DNA damage response genes associated with orgenes is judged to be the risk of radiotherapy-related cancer. gan-wide radiation cancer risk would be the most likely A major theme developing in the whole field of cancer source of major interindividual differences in radiation genetics is the interaction and potential impact of more response.
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