Advertisement

Genetic Basis of Normal Tissue Radiosensitivity and Late Toxicity in Breast Cancer

  • Dhara MacDermed
Chapter
Part of the Medical Radiology book series (MEDRAD)

Abstract

Individual variations in sensitivity to radiation toxicity are clinically important, but their genetic basis is poorly understood. Single nucleotide polymorphisms (SNPs) in many genes have been correlated to a higher risk of acute or late radiation toxicity. This chapter discusses cellular studies predictive of radiation sensitivity and studies of specific genes of interest, with a focus on breast cancer research. Radiogenomics studies of ATM, XRCC1, and TGFB1 are discussed, and other genes and SNPs associated with radiation toxicity are summarized. Recent results of the RAPPER study indicate that the candidate gene approach is inadequate to discover clinically useful indicators of radiation sensitivity. Genome-wide association studies (GWAS) and international collaborations may hold the key to future progress in this area.

Keywords

Breast Cancer Patient BRCA2 Mutation Late Toxicity Radiation Sensitivity Nijmegen Breakage Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Ahn J, Ambrosone CB, Kanetsky PA, Tian C, Lehman TA, Kropp S, Helmbold I et al (2006) Polymorphisms in genes related to oxidative stress (CAT, MnSOD, MPO, and eNOS) and acute toxicities from radiation therapy following lumpectomy for breast cancer. Clin Cancer Res Official J Am Assoc Cancer Res 12(23):7063–7070. doi: 10.1158/1078-0432.CCR-06-0039 CrossRefGoogle Scholar
  2. Alsbeih G, Al-Harbi N, Al-Hadyan K, El-Sebaie M, Al-Rajhi N (2010) Association between normal tissue complications after radiotherapy and polymorphic variations in TGFB1 and XRCC1 genes. Radiat Res 173(4):505–511. doi: 10.1667/RR1769.1 CrossRefPubMedGoogle Scholar
  3. Alsner J, Andreassen CN (2008) Genetic markers for prediction of normal tissue toxicity after radiotherapy. Semin Radiat Oncol 18(2):126–135CrossRefPubMedGoogle Scholar
  4. Ambrosone CB, Tian C, Ahn J, Kropp S, Helmbold I, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Chang-Claude J (2006) Genetic predictors of acute toxicities related to radiation therapy following lumpectomy for breast cancer: a case-series study. Breast Cancer Res (BCR) 8(4):R40. doi: 10.1186/bcr1526 CrossRefGoogle Scholar
  5. Andreassen CN, Alsner J, Overgaard M, Sørensen FB, Overgaard J (2006a) Risk of radiation-induced subcutaneous fibrosis in relation to single nucleotide polymorphisms in TGFB1, SOD2, XRCC1, XRCC3, APEX and ATM—a study based on dna from formalin fixed paraffin embedded tissue samples. Int J Radiat Biol 82(8):577–586. doi: 10.1080/09553000600876637 CrossRefPubMedGoogle Scholar
  6. Andreassen CN, Overgaard J, Alsner J, Overgaard M, Herskind C, Cesaretti JA, Atencio DP, Green S et al (2006b) ATM sequence variants and risk of radiation-induced subcutaneous fibrosis after postmastectomy radiotherapy. Int J Radiat Oncol Biol Phys 64(3):776–783. doi: 10.1016/j.ijrobp.2005.09.014 CrossRefPubMedGoogle Scholar
  7. Andreassen CN, Alsner J, Overgaard J, Herskind C, Haviland J, Owen R, Homewood J, Bliss J, Yarnold J (2005) TGFB1 polymorphisms are associated with risk of late normal tissue complications in the breast after radiotherapy for early breast cancer. Radiother Oncol J EurSocTher Radiol Oncol 75(1):18–21. doi: 10.1016/j.radonc.2004.12.012 CrossRefGoogle Scholar
  8. Andreassen CN, Alsner J, Overgaard M, Overgaard J (2003) Prediction of normal tissue radiosensitivity from polymorphisms in candidate genes. Radiother Oncol J Eur Soc Ther Radiol Oncol 69(2):127–135CrossRefGoogle Scholar
  9. Angèle S, Romestaing P, Moullan N, Vuillaume M, Chapot B, Friesen M, Jongmans W et al (2003) ATM haplotypes and cellular response to DNA damage: association with breast cancer risk and clinical radiosensitivity. Cancer Res 63(24):8717–8725PubMedGoogle Scholar
  10. Appleby JM, Barber JB, Levine E, Varley JM, Taylor AM, Stankovic T, Heighway J, Warren C, Scott D (1997) Absence of mutations in the ATM gene in breast cancer patients with severe responses to radiotherapy. Br J Cancer 76(12):1546–1549CrossRefPubMedCentralPubMedGoogle Scholar
  11. Azria D, Ozsahin M, Kramar A, Peters S, Atencio DP, Crompton NEA, Mornex F et al (2008) Single nucleotide polymorphisms, apoptosis, and the development of severe late adverse effects after radiotherapy. Clin Cancer Res Official J Am Assoc Cancer Res 14(19):6284–6288. doi: 10.1158/1078-0432.CCR-08-0700 CrossRefGoogle Scholar
  12. Badie C, Dziwura S, Raffy C, Tsigani T, Alsbeih G, Moody J, Finnon P, Levine E, Scott D, Bouffler S (2008) Aberrant CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment. Br J Cancer 98(11):1845–1851. doi: 10.1038/sj.bjc.6604381 CrossRefPubMedCentralPubMedGoogle Scholar
  13. Baeyens A, Thierens H, Claes K, Poppe B, de Ridder L, Vral A (2004) Chromosomal radiosensitivity in BRCA1 and BRCA2 mutation carriers. Int J Radiat Biol 80(10):745–756CrossRefPubMedGoogle Scholar
  14. Barnett GC, Coles CE, Burnet NG, Pharoah PDP, Wilkinson J, West CML, Elliott RM, Baynes C, Dunning AM (2010) No association between SNPs regulating TGF-Β1 secretion and late radiotherapy toxicity to the breast: results From the RAPPER study. Radiother Oncol J Eur Soc Ther Radiol Oncol 97(1):9–14. doi: 10.1016/j.radonc.2009.12.006 CrossRefGoogle Scholar
  15. Barnett GC, Coles CE, Elliott RM, Baynes C, Luccarini C, Conroy D, Wilkinson JS et al (2012) Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study. Lancet Oncol 13(1):65–77. doi: 10.1016/S1470-2045(11)70302-3 CrossRefPubMedGoogle Scholar
  16. Brem R, Cox DG, Chapot B, Moullan N, Romestaing P, Gérard J-P, Pisani P, Hall J (2006) The XRCC1 -77T→C variant: haplotypes, breast cancer risk, response to radiotherapy and the cellular response to DNA damage. Carcinogenesis 27(12):2469–2474. doi: 10.1093/carcin/bgl114 CrossRefPubMedGoogle Scholar
  17. Bremer M, Klöpper K, Yamini P, Bendix-Waltes R, Dörk T, Karstens JH (2003) Clinical radiosensitivity in breast cancer patients carrying pathogenic ATM gene mutations: no observation of increased radiation-induced acute or late effects. Radiother Oncol J Eur Soc Ther Radiol Oncol 69(2):155–160CrossRefGoogle Scholar
  18. Buchholz TA, Wu X, Hussain A, Tucker SL, Mills GB, Haffty B, Bergh S, Story M, Geara FB, Brock WA (2002) Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2. Int J Cancer J Int Du Cancer 97(5):557–561CrossRefGoogle Scholar
  19. Burnet NG, Nyman J, Turesson I, Wurm R, Yarnold JR, Peacock JH (1992) Prediction of normal-tissue tolerance to radiotherapy from in-vitro cellular radiation sensitivity. Lancet 339(8809):1570–1571CrossRefPubMedGoogle Scholar
  20. Cesaretti JA, Stock RG, Lehrer S, Atencio DA, Bernstein JL, Stone NN, Wallenstein S et al (2005) ATM sequence variants are predictive of adverse radiotherapy response among patients treated for prostate cancer. Int J Radiat Oncol Biol Phys 61(1):196–202. doi: 10.1016/j.ijrobp.2004.09.031 CrossRefPubMedGoogle Scholar
  21. Chang-Claude J, Ambrosone CB, Lilla C (2009) Genetic polymorphisms in DNA repair and damage response genes and late normal tissue complications of radiotherapy for breast cancer. Br J Cancer 100(10):1680–1686CrossRefPubMedCentralPubMedGoogle Scholar
  22. Chang-Claude J, Popanda O, Tan X-L, Kropp S, Helmbold I, von Fournier D, Haase W et al (2005) Association between polymorphisms in the DNA repair genes, XRCC1, APE1, and XPD and acute side effects of radiotherapy in breast cancer patients. Clin Cancer Res Official J Am Assoc Cancer Res 11(13):4802–4809. doi: 10.1158/1078-0432.CCR-04-2657 CrossRefGoogle Scholar
  23. Chistiakov DA, Voronova NV, Chistiakov AP (2009) Ligase IV syndrome. Eur J Med Genet 52(6):373–378. doi: 10.1016/j.ejmg.2009.05.009 CrossRefPubMedGoogle Scholar
  24. Clarke RA, Goozee GR, Birrell G, Fang ZM, Hasnain H, Lavin M, Kearsley JH (1998) Absence of ATM truncations in patients with severe acute radiation reactions. Int J Radiat Oncol Biol Phys 41(5):1021–1027CrossRefPubMedGoogle Scholar
  25. De Ruyck K, Van Eijkeren M, Claes K, Bacher K, Vral A, De Neve W, Thierens H (2006) TGFbeta1 polymorphisms and late clinical radiosensitivity in patients treated for gynecologic tumors. Int J Radiat Oncol Biol Phys 65(4):1240–1248. doi: 10.1016/j.ijrobp.2006.03.047 CrossRefPubMedGoogle Scholar
  26. Edvardsen H, Tefre T, Jansen L, Vu P, Haffty BG, Fosså SD, Kristensen VN, Børresen-Dale A-L (2007) Linkage disequilibrium pattern of the ATM gene in breast cancer patients and controls; association of SNPs and haplotypes to radio-sensitivity and post-lumpectomy local recurrence. Radiat Oncol (Lond Engl) 2:25. doi: 10.1186/1748-717X-2-25 CrossRefGoogle Scholar
  27. Ernestos B, Nikolaos P, Koulis G, Eleni R, Konstantinos B, Alexandra G, Michael K (2010) Increased chromosomal radiosensitivity in women carrying BRCA1/BRCA2 mutations assessed with the G2 assay. Int J Radiat Oncol Biol Phys 76(4):1199–1205. doi: 10.1016/j.ijrobp.2009.10.020 CrossRefPubMedGoogle Scholar
  28. Falvo Elisabetta, Strigari Lidia, Citro Gennaro, Giordano Carolina, Boboc Genoveva, Fabretti Fabiana, Bruzzaniti Vicente et al (2012) SNPs in DNA repair or oxidative stress genes and late subcutaneous fibrosis in patients following single shot partial breast irradiation. J Exp Clin Cancer Res CR 31:7. doi: 10.1186/1756-9966-31-7 CrossRefGoogle Scholar
  29. Fogarty GB, Muddle R, Sprung CN, Chen W, Duffy D, Sturm RA, McKay MJ (2010) Unexpectedly severe acute radiotherapy side effects are associated with single nucleotide polymorphisms of the melanocortin-1 receptor. Int J Radiat Oncol Biol Phys 77(5):1486–1492CrossRefPubMedGoogle Scholar
  30. Giotopoulos G, Symonds RP, Foweraker K, Griffin M, Peat I, Osman A, Plumb M (2007) The late radiotherapy normal tissue injury phenotypes of telangiectasia, fibrosis and atrophy in breast cancer patients have distinct genotype-dependent causes. Br J Cancer 96(6):1001–1007. doi: 10.1038/sj.bjc.6603637 CrossRefPubMedCentralPubMedGoogle Scholar
  31. Girard P-M, Kysela B, Härer CJ, Doherty AJ, Jeggo PA (2004) Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms. Hum Mol Gen 13(20):2369–2376. doi: 10.1093/hmg/ddh274 CrossRefPubMedGoogle Scholar
  32. Green H, Ross G, Peacock J, Owen R, Yarnold J, Houlston R (2002) Variation in the manganese superoxide dismutase gene (SOD2) is not a major cause of radiotherapy complications in breast cancer patients. Radiother Oncol J Eur Soc Ther Radiol Oncol 63(2):213–216CrossRefGoogle Scholar
  33. Hall EJ, Schiff PB, Hanks GE, Brenner DJ, Russo J, Chen J, Sawant SG, Pandita TK (1998) A preliminary report: frequency of a-T heterozygotes among prostate cancer patients with severe late responses to radiation therapy. Cancer J Sci Am 4(6):385–389PubMedGoogle Scholar
  34. Hall EJ, Giaccia A (2011) Radiobiology for the radiologist, 7th edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  35. Ho AY, Fan G, Atencio DP, Green S, Formenti SC, Haffty BG, Iyengar P et al (2007) Possession of ATM sequence variants as predictor for late normal tissue responses in breast cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 69(3):677–684. doi: 10.1016/j.ijrobp.2007.04.012 CrossRefPubMedGoogle Scholar
  36. Iannuzzi CM, Atencio DP, Green S, Stock RG, Rosenstein BS (2002) ATM mutations in female breast cancer patients predict for an increase in radiation-induced late effects. Int J Radiat Oncol Biol Phys 52(3):606–613CrossRefPubMedGoogle Scholar
  37. Isomura M, Oya N, Tachiiri S, Kaneyasu Y, Nishimura Y, Akimoto T, Hareyama M et al (2008) IL12RB2 and ABCA1 genes are associated with susceptibility to radiation dermatitis. Clin Cancer Res Official J Am Assoc Cancer Res 14(20):6683–6689. doi: 10.1158/1078-0432.CCR-07-4389 CrossRefGoogle Scholar
  38. Kerns SL, Ostrer H, Stock R, Li W, Moore J, Pearlman A, Campbell C et al (2010) Genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 78(5):1292–1300. doi: 10.1016/j.ijrobp.2010.07.036 CrossRefPubMedCentralPubMedGoogle Scholar
  39. Kuptsova N, Chang-Claude J, Kropp S, Helmbold I, Schmezer P, von Fournier D, Haase W et al (2008) Genetic predictors of long-term toxicities after radiation therapy for breast cancer. Int J Cancer J Int Du Cancer 122(6):1333–1339. doi: 10.1002/ijc.23138 CrossRefGoogle Scholar
  40. Leong T, Whitty J, Keilar M, Mifsud S, Ramsay J, Birrell G, Venter D, Southey M, McKay M (2000) Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients. Int J Radiat Oncol Biol Phys 48(4):959–965CrossRefPubMedGoogle Scholar
  41. Mangoni M, Bisanzi S, Carozzi F, Sani C, Biti G, Livi L, Barletta E, Costantini AS, Gorini G (2011) Association between genetic polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT genes and radiosensitivity in breast cancer patients. Int J Radiat Oncol Biol Phys 81(1):52–58. doi: 10.1016/j.ijrobp.2010.04.023 CrossRefPubMedGoogle Scholar
  42. Meyer A, Dörk T, Bogdanova N, Brinkhaus M-J, Wiese B, Hagemann J, Serth J et al (2009) TGFB1 gene polymorphism Leu10Pro (C.29T>C), prostate cancer incidence and quality of life in patients treated with brachytherapy. World J Urol 27(3):371–377. doi: 10.1007/s00345-008-0354-0 CrossRefPubMedGoogle Scholar
  43. Moullan N, Cox DG, Angèle S, Romestaing P, Gérard J-P, Hall J (2003) Polymorphisms in the DNA repair gene XRCC1, breast cancer risk, and response to radiotherapy. Cancer epidemiology, biomarkers and prevention: a publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 12(11):1168–1174Google Scholar
  44. Oppitz U, Bernthaler U, Schindler D, Sobeck A, Hoehn H, Platzer M, Rosenthal A, Flentje M (1999) Sequence analysis of the ATM gene in 20 patients with RTOG grade 3 or 4 acute and/or late tissue radiation side effects. Int J Radiat Oncol Biol Phys 44(5):981–988CrossRefPubMedGoogle Scholar
  45. Parliament MB, Murray D (2010) Single nucleotide polymorphisms of DNA repair genes as predictors of radioresponse. Semin Radiat Oncol 20(4):232–240. doi: 10.1016/j.semradonc.2010.05.003 CrossRefPubMedGoogle Scholar
  46. Peters CA, Stock RG, Cesaretti JA, Atencio DP, Peters S, Burri RJ, Stone NN, Ostrer H, Rosenstein BS (2008) TGFB1 single nucleotide polymorphisms are associated with adverse quality of life in prostate cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 70(3):752–759. doi: 10.1016/j.ijrobp.2007.05.023 CrossRefPubMedGoogle Scholar
  47. Pierce LJ, Strawderman M, Narod SA, Oliviotto I, Eisen A, Dawson L, Gaffney D et al (2000) Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol Official J Am Soc Clin Oncol 18(19):3360–3369Google Scholar
  48. Popanda O, Tan X-L, Ambrosone CB, Kropp S, Helmbold I, von Fournier D, Haase W et al (2006) Genetic polymorphisms in the DNA double-strand break repair genes XRCC3, XRCC2, and NBS1 are not associated with acute side effects of radiotherapy in breast cancer patients. Cancer epidemiology, biomarkers and prevention: a publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 15(5):1048–1050. doi:10.1158/1055-9965.EPI-06-0046Google Scholar
  49. Pratesi N, Mangoni M, Mancini I, Paiar F (2011) Association between single nucleotide polymorphisms in the XRCC1 and RAD51 genes and clinical radiosensitivity in head and neck cancer. Radiother Oncol 99(3):356–361CrossRefPubMedGoogle Scholar
  50. Quarmby S, Fakhoury H, Levine E, Barber J, Wylie J, Hajeer AH, West C, Stewart A, Magee B, Kumar S (2003) Association of transforming growth factor beta-1 single nucleotide polymorphisms with radiation-induced damage to normal tissues in breast cancer patients. Int J Radiat Biol 79(2):137–143CrossRefPubMedGoogle Scholar
  51. Ramsay J, Birrell G, Lavin M (1998) Testing for mutations of the ataxia telangiectasia gene in radiosensitive breast cancer patients. Radiother Oncol J Eur Soc Ther Radiol Oncol 47(2):125–128CrossRefGoogle Scholar
  52. Shanley S, McReynolds K, Ardern-Jones A, Ahern R, Fernando I, Yarnold J, Evans G et al (2006) Late toxicity is not increased in BRCA1/BRCA2 mutation carriers undergoing breast radiotherapy in the United Kingdom. Clin Cancer Res Official J Am Assoc Cancer Res 12(23):7025–7032. doi: 10.1158/1078-0432.CCR-06-1244 CrossRefGoogle Scholar
  53. Shayeghi M, Seal S, Regan J, Collins N, Barfoot R, Rahman N, Ashton A et al (1998) Heterozygosity for mutations in the ataxia telangiectasia gene is not a major cause of radiotherapy complications in breast cancer patients. Br J Cancer 78(7):922–927CrossRefPubMedCentralPubMedGoogle Scholar
  54. Sterpone S, Cornetta T, Padua L, Mastellone V, Giammarino D, Testa A, Tirindelli D, Cozzi R, Donato V (2010) DNA repair capacity and acute radiotherapy adverse effects in Italian breast cancer patients. Mutat Res 684(1–2):43–48. doi: 10.1016/j.mrfmmm.2009.11.009 CrossRefPubMedGoogle Scholar
  55. Suga T, Ishikawa A, Kohda M, Otsuka Y, Yamada S, Yamamoto N, Shibamoto Y et al (2007) Haplotype-based analysis of genes associated with risk of adverse skin reactions after radiotherapy in breast cancer patients. Int J Radiat Oncol Biol Phys 69(3):685–693. doi: 10.1016/j.ijrobp.2007.06.021 CrossRefPubMedGoogle Scholar
  56. Suga T, Iwakawa M, Tsuji H, Ishikawa H, Oda E, Noda S, Otsuka Y et al (2008) Influence of multiple genetic polymorphisms on genitourinary morbidity after carbon ion radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 72(3):808–813. doi: 10.1016/j.ijrobp.2008.01.029 CrossRefPubMedGoogle Scholar
  57. Tan X-L, Popanda O, Ambrosone CB, Kropp S, Helmbold I, von Fournier D, Haase W et al (2006) Association between TP53 and P21 genetic polymorphisms and acute side effects of radiotherapy in breast cancer patients. Breast Cancer Res Treat 97(3):255–262. doi: 10.1007/s10549-005-9119-2 CrossRefPubMedGoogle Scholar
  58. Weissberg JB, Huang DD, Swift M (1998) Radiosensitivity of normal tissues in ataxia-telangiectasia heterozygotes. Int J Radiat Oncol Biol Phys 42(5):1133–1136CrossRefPubMedGoogle Scholar
  59. West CM, Davidson SE, Elyan SA, Valentine H, Roberts SA, Swindell R, Hunter RD (2001) Lymphocyte radiosensitivity is a significant prognostic factor for morbidity in carcinoma of the cervix. Int J Radiat Oncol Biol Phys 51(1):10–15CrossRefPubMedGoogle Scholar
  60. West CML, Barnett GC, Dunning AM, Elliott RM, Burnet NG, Newman WG (2010). In: Newman WG (ed) Pharmacogenetics: making cancer treatment safer and more effective. Springer, Netherlands, Dordrecht. doi: 10.1007/978-90-481-8618-1_9
  61. Yuan X, Liao Z, Liu Z, Wang L-E, Tucker SL, Mao L, Wang XS et al (2009) Single nucleotide polymorphism at Rs1982073:T869C of the TGFbeta 1 gene is associated with the risk of radiation pneumonitis in patients with non-small-cell lung cancer treated with definitive radiotherapy. J Clin Oncol Official J Am Soc Clin Oncol 27(20):3370–3378. doi: 10.1200/JCO.2008.20.6763 CrossRefGoogle Scholar
  62. Zhang L, Yang M, Bi N, Fang M, Sun T, Ji W, Tan W et al (2010) ATM polymorphisms are associated with risk of radiation-induced pneumonitis. Int J Radiat Oncol Biol Phys 77(5):1360–1368. doi: 10.1016/j.ijrobp.2009.07.1675 CrossRefPubMedGoogle Scholar
  63. Zschenker O, Raabe A, Boeckelmann IK, Borstelmann S, Szymczak S, Wellek S, Rades D et al (2010) Association of single nucleotide polymorphisms in ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with clinical and cellular radiosensitivity. Radiother Oncol J Eur Soc Ther Radiol Onco 97(1):26–32. doi: 10.1016/j.radonc.2010.01.016 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.St. Charles Cancer Treatment CenterBendUSA

Personalised recommendations