Abstract
Genetic factors are likely to affect individual cancer risk, but few quantitative estimates of heritability are available. Public health radiation protection policies do not in general take this potentially important source of variation in risk into account. Two surrogate cellular assays that relate to cancer susceptibility have been developed to gain an insight into the role of genetics in determining individual variation in radiosensitivity. These flow cytometric assays for apoptosis induction and cell cycle delay following radiation are sufficiently sensitive to distinguish lymphocytes from a healthy donor population from those of a sample of obligate carriers of ATM mutations (P = 0.01 and P = 0.02, respectively). Analysis of 54 unselected twin pairs (38 dizygotic, 16 monozygotic) indicated much greater intrapair correlation in response in monozygotic than in dizygotic pairs. Structural equation modelling indicated that models including unique environmental factors only fitted the data less well than those incorporating two or more of additive genetic factors, common environmental factors and unique environmental factors. A model incorporating additive genetic factors and unique environmental factors yielded estimates of heritability for the two traits of 68% (95% CI 40–82%, cell cycle) and 59% (95% CI 22–79%, apoptosis). Thus, these data suggest that genetic factors contribute significantly to human variation in these two measures of radiosensitivity that relate to cancer susceptibility.
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References
Baker SG, Lichtenstein P, Kaprio J, Holm N (2005) Genetic susceptibility to prostate, breast and colorectal cancer among Nordic twins. Biometrics 61:55–63
Barber JBP, West CML, Kiltie AE, Roberts SA, Scott D (2000) Detection of individual differences in radiation-induced apoptosis of peripheral blood lymphocytes in normal individuals, ataxia telangiectasia homozygotes and heterozygotes, and breast cancer patients after radiotherapy. Radiat Res 153:570–578
Berwick M, Vineis P (2000) Markers of DNA repair and susceptibility to cancer in humans: an epidemiological review. J Natl Cancer Inst 92:874–897
Boffetta P, van der Hel O, Norppa H, Fabianova E, Fucic A, Gundy S, Lazutka J, Cebulska-Wasilewska A, Puskailerova D, Znaor A et al (2007) Chromosomal aberrations and cancer risk: results of a cohort study from central Europe. Am J Epidemiol 165:36–43
Boomsma D, Busjahn A, Peltonen L (2002) Classical twin studies and beyond. Nat Rev Genet 3:872–882
Borgmann K, Haeberle D, Doerk T, Busjahn A, Stephan G, Dikomey E (2007) Genetic determination of chromosomal radiosensitivities in Go and G2 phase human lymphocytes. Radiother Oncol 83:196–202
Brock MV, Herman JG, Baylin SB (2007) Cancer as a manifestation of aberrant chromatin structure. Cancer J 13:3–8
Camplejohn RS, Gilchrist R, Easton D, McKenzie-Edwards E, Barnes DM, Eccles DM, Arden-Jones A, Hodgson SV, Duddy PM, Eeles RA (2003) Apoptosis, ageing and cancer susceptibility. Br J Cancer 88:487–490
Camplejohn RS, Hodgson S, Carter N, Kato BS, Spector TD (2006) Heritability of DNA-damage-induced apoptosis and its relationship with age in lymphocytes from female twins. Br J Cancer 95:520–524
Dixon AL, Liang L, Moffatt MF, Chen W, Heath S, Wong KCC, Taylor J, Burnett E, Gut I, Farrall M et al (2007) A genome-wide association study of global gene expression. Nature Genet 39:1202–1207
Docherty Z, Georgiou A, Langman C, Kesterton I, Rose S, Camplejohn R, Ball J, Barwell J, Gilchrist R, Pangon L et al (2007) Is chromosome radiosensitivity and apoptotic response to irradiation correlated with cancer susceptibility? Int J Radiat Biol 83:1–12
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102:10604–10609
Greenman C, Stephens P, Smith R et al (2007) Patterns of somatic mutation in human cancer genomes. Nature 446:153–158
Gutiérrez-EnrÍquez S, Fernet M, Dork T, Bremer M, Lauge A, Stoppa-Lyonnet D, Moullan N, Angele S, Hall J (2004) Functional consequences of ATM sequence variants for chromosomal radiosensitivity. Genes Chromosomes Cancer 40:109–119
Horvath MM, Wang X, Resnick MA, Bell DA (2007) Divergent evolution of human p53 binding sites: cell cycle versus apoptosis. PLoS Genet 3:e127
Hu JJ, Smith TR, Miller MS, Lohman K, Case LD (2002) Genetic regulation of ionizing radiation sensitivity and breast cancer risk. Environ Mol Mutagen 39:208–215
ICRP (2007) The 2007 Recommendations of the International Commission on Radiological Protection. ICRP publication 103. Ann ICRP 37(2–4):1–332
Iwasaki T, Robertson N, Tsigani T, Finnon P, Scott D, Levine E, Badie C, Bouffler S (2008) Lymphocyte telomere length correlates with in vitro radiosensitivity in breast cancer cases but is not predictive of acute normal tissue reactions to radiotherapy. Int J Radiat Biol 84:277–284
Johnson N, Fletcher O, Palles C, Rudd M, Webb E, Sellick G, Dos Santos Silva I, McCormack V, Gibson L, Fraser A et al (2007) Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility. Hum Mol Genet 16:1051–1057
Kaprio J, Pulkkinen J, Rose RJ (2002) Genetic and environmental factors in health-related behaviours: studies on Finnish twins and twin families. Twin Res 5:366–371
Lavin MF, LePoidevin P, Bates P (1992) Enhanced levels of radiation-induced G2 phase delay in ataxia telangiectasia heterozygotes. Cancer Genet Cytogenet 60:183–187
Lavin MF, Bennett I, Ramsey J, Gardiner RA, Seymour GJ, Farrell A, Walsh M (1994) Identification of a potentially radiosensitive subgroup among patients with breast cancer. J Nat Cancer Inst 86:1627–1634
Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer – analyses of cohorts of twins from Sweden, Denmark and Finland. N Engl J Med 343:78–85
Lisowska H, Lankoff A, Wieczorek A, Florek A, Kuszewski T, Gozdz S, Wojcik A (2006) Enhanced chromosomal radiosensitivity in peripheral blood lymphocytes of larynx cancer patients. Int J Radiat Oncol Biol Phys 66:1245–1252
Mitelman F, Johansson B, Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7:233–245
Neale MC, Cardon LR (1992) Methodology for genetic studies of twins and families. Kluwer Academic Publishers, Dordrecht
Norppa H, Bonassi S, Hansteen IL, Hagmar L, Stromberg U, Rossner P, Boffetta P, Lindholm C, Gundy S, Lazutka J et al (2006) Chromosomal aberrations and SCEs as biomarkers of cancer risk. Mutat Res 600:37–45
O’Donovan MR, Freemantle MR, Hull G, Bell DA, Arlett CP, Cole J (1995) Extended-term cultures of human T-lymphocytes: a practical alternative to primary human lymphocytes for use in genotoxicity testing. Mutagenesis 10:189–201
Roberts SA, Spreadborough AR, Bulman B, Barber JB, Evans DG, Scott D (1999) Heritability of cellular radiosensitivity: a marker of low-penetrance predisposition genes in breast cancer? Am J Human Genet 65:784–794
Scott D, Spreadborough AR, Jones LA, Roberts SA, Moore CJ (1996) Chromosomal radiosensitivity in G2 phase lymphocytes as an indicator of cancer predisposition. Radiat Res 145:3–16
Scott D (2004) Chromosomal radiosensitivity and low penetrance predisposition to cancer. Cytogenet Genome Res 104:365–370
Spitz MR, Wei Q, Dong Q, Amos CI, Wu X (2003) Genetic susceptibility to lung cancer: the role of DNA damage and repair. Cancer Epidemiol Biomarkers Prev 12:689–698
Wu X, Spitz MR, Amos CI, Lin J, Shao L, Gu J, deAndrade M, Benowitz ML, Shields PG, Savan GE (2006) Mutagen sensitivity has high heritability: evidence from a twin study. Cancer Res 66:5993–5996
Zhao H, Spitz MR, Tomlinson GE, Zhang H, Minna JD, Wu X (2001) γ-radiation-induced G2 delay, apoptosis and p53 response as potential susceptibility markers for lung cancer. Cancer Res 61:7819–7824
Acknowledgments
We wish to thank Richard Doull of MRC Harwell for irradiations, Asif Ahmed for technical assistance in the early stages of this work and Prof. Malcolm Taylor of the University of Birmingham for providing AT carrier lymphocytes. This work was funded by the Department of Health Radiation Protection Research Programme, grants RRX 83 and RRX 111. Data collection in the FinnTwin16 study has been supported by the National Institute on Alcohol Abuse and Alcoholism (grants AA-08315 and AA-12502), the Academy of Finland (Grants 44069 and 100499) and the Academy of Finland Centre of Excellence in Complex Disease Genetics.
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Finnon, P., Robertson, N., Dziwura, S. et al. Evidence for significant heritability of apoptotic and cell cycle responses to ionising radiation. Hum Genet 123, 485–493 (2008). https://doi.org/10.1007/s00439-008-0500-1
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DOI: https://doi.org/10.1007/s00439-008-0500-1