Breast Cancer Research and Treatment

, Volume 117, Issue 1, pp 17–24 | Cite as

Genomic instability demonstrates similarity between DCIS and invasive carcinomas

  • Christopher M. Heaphy
  • Marco Bisoffi
  • Nancy E. Joste
  • Kathy B. Baumgartner
  • Richard N. Baumgartner
  • Jeffrey K. Griffith
Preclinical study

Abstract

Purpose To assess telomere DNA content (TC) and the number of sites of allelic imbalance (AI) as a function of breast cancer progression. Experimental design TC and AI were determined in 54 histologically normal tissues, 10 atypical ductal hyperplasias (ADH), 122 in situ ductal carcinomas (DCIS) and 535 invasive carcinomas (Stage I–IIIA). Results TC was altered in ADH lesions (20%), DCIS specimens (53%) and invasive carcinomas (51%). The mean number of sites of AI was 0.26 in histologically normal group tissue, increased to 1.00 in ADH, 2.94 in DCIS, and 3.07 in invasive carcinomas. All groups were statistically different from the histologically normal group (P < 0.001 for each); however, there was no difference between DCIS and the invasive groups. Conclusions Genomic instability increases in ADH and plateaus in DCIS without further increase in the invasive carcinomas, supporting the notion that invasive carcinomas evolve from or in parallel with DCIS.

Keywords

Allelic imbalance Breast cancer Ductal carcinoma in situ Genomic instability Telomere DNA content 

References

  1. 1.
    Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396:643–649. doi:10.1038/25292 PubMedCrossRefGoogle Scholar
  2. 2.
    Simpson PT, Reis-Filho JS, Gale T, Lakhani SR (2005) Molecular evolution of breast cancer. J Pathol 205:248–254. doi:10.1002/path.1691 PubMedCrossRefGoogle Scholar
  3. 3.
    Allred DC, Mohsin SK, Fuqua SA (2001) Histological and biological evolution of human premalignant breast disease. Endocr Relat Cancer 8:47–61. doi:10.1677/erc.0.0080047 PubMedCrossRefGoogle Scholar
  4. 4.
    Lo AW, Sabatier L, Fouladi B, Pottier G, Ricoul M, Murnane JP (2002) DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line. Neoplasia 4:531–538. doi:10.1038/sj.neo.7900267 PubMedCrossRefGoogle Scholar
  5. 5.
    O’Hagan RC, Chang S, Maser RS, Mohan R, Artandi SE, Chin L et al (2002) Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2:149–155. doi:10.1016/S1535-6108(02)00094-6 PubMedCrossRefGoogle Scholar
  6. 6.
    Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB et al (1992) Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J 11:1921–1929PubMedGoogle Scholar
  7. 7.
    Chin K, de Solorzano CO, Knowles D, Jones A, Chou W, Rodriguez EG et al (2004) In situ analyses of genome instability in breast cancer. Nat Genet 36:984–988. doi:10.1038/ng1409 PubMedCrossRefGoogle Scholar
  8. 8.
    Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD et al (1988) A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA 85:6622–6626. doi:10.1073/pnas.85.18.6622 PubMedCrossRefGoogle Scholar
  9. 9.
    de Lange T (2002) Protection of mammalian telomeres. Oncogene 21:532–540. doi:10.1038/sj.onc.1205080 PubMedCrossRefGoogle Scholar
  10. 10.
    Smogorzewska A, de Lange T (2004) Regulation of telomerase by telomeric proteins. Annu Rev Biochem 73:177–208. doi:10.1146/annurev.biochem.73.071403.160049 PubMedCrossRefGoogle Scholar
  11. 11.
    de Lange T, Shiue L, Myers RM, Cox DR, Naylor SL, Killery AM et al (1990) Structure and variability of human chromosome ends. Mol Cell Biol 10:518–527PubMedGoogle Scholar
  12. 12.
    Saltman D, Morgan R, Cleary ML, de Lange T (1993) Telomeric structure in cells with chromosome end associations. Chromosoma 102:121–128. doi:10.1007/BF00356029 PubMedCrossRefGoogle Scholar
  13. 13.
    Hande MP, Samper E, Lansdorp P, Blasco MA (1999) Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J Cell Biol 144:589–601. doi:10.1083/jcb.144.4.589 PubMedCrossRefGoogle Scholar
  14. 14.
    Olovnikov AM (1973) A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 41:181–190. doi:10.1016/0022-5193(73)90198-7 PubMedCrossRefGoogle Scholar
  15. 15.
    Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G et al (2000) Control of human telomere length by TRF1 and TRF2. Mol Cell Biol 20:1659–1668. doi:10.1128/MCB.20.5.1659-1668.2000 PubMedCrossRefGoogle Scholar
  16. 16.
    Bohr VA, Anson RM (1995) DNA damage, mutation and fine structure DNA repair in aging. Mutat Res 338:25–34PubMedGoogle Scholar
  17. 17.
    Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015. doi:10.1126/science.7605428 PubMedCrossRefGoogle Scholar
  18. 18.
    Meeker AK, Argani P (2004) Telomere shortening occurs early during breast tumorigenesis: a cause of chromosome destabilization underlying malignant transformation? J Mammary Gland Biol Neoplasia 9:285–296. doi:10.1023/B:JOMG.0000048775.04140.92 PubMedCrossRefGoogle Scholar
  19. 19.
    Meeker AK, Hicks JL, Iacobuzio-Donahue CA, Montgomery EA, Westra WH, Chan TY et al (2004) Telomere length abnormalities occur early in the initiation of epithelial carcinogenesis. Clin Cancer Res 10:3317–3326. doi:10.1158/1078-0432.CCR-0984-03 PubMedCrossRefGoogle Scholar
  20. 20.
    Meeker AK, Hicks JL, Gabrielson E, Strauss WM, De Marzo AM, Argani P (2004) Telomere shortening occurs in subsets of normal breast epithelium as well as in situ and invasive carcinoma. Am J Pathol 164:925–935PubMedGoogle Scholar
  21. 21.
    Heaphy CM, Bisoffi M, Fordyce CA, Haaland CM, Hines WC, Joste NE et al (2006) Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. Int J Cancer 119:108–116. doi:10.1002/ijc.21815 PubMedCrossRefGoogle Scholar
  22. 22.
    Fordyce CA, Heaphy CM, Bisoffi M, Wyaco JL, Joste NE, Mangalik A et al (2006) Telomere content correlates with stage and prognosis in breast cancer. Breast Cancer Res Treat 99:193–202. doi:10.1007/s10549-006-9204-1 PubMedCrossRefGoogle Scholar
  23. 23.
    Heaphy CM, Baumgartner KB, Bisoffi M, Baumgartner RN, Griffith JK (2007) Telomere DNA content predicts breast cancer free survival interval. Clin Cancer Res 13:7037–7043. doi:10.1158/1078-0432.CCR-07-0432 PubMedCrossRefGoogle Scholar
  24. 24.
    Balmain A, Gray J, Ponder B (2003) The genetics and genomics of cancer. Nat Genet 33(Suppl):238–244. doi:10.1038/ng1107 PubMedCrossRefGoogle Scholar
  25. 25.
    Miyakis S, Spandidos DA (2002) Allelic loss in breast cancer. Cancer Detect Prev 26:426–434. doi:10.1016/S0361-090X(02)00128-9 PubMedCrossRefGoogle Scholar
  26. 26.
    Farabegoli F, Champeme MH, Bieche I, Santini D, Ceccarelli C, Derenzini M et al (2002) Genetic pathways in the evolution of breast ductal carcinoma in situ. J Pathol 196:280–286. doi:10.1002/path.1048 PubMedCrossRefGoogle Scholar
  27. 27.
    Ellsworth RE, Ellsworth DL, Love B, Patney HL, Hoffman LR, Kane J et al (2007) Correlation of levels and patterns of genomic instability with histological grading of DCIS. Ann Surg Oncol 14:3070–3077. doi:10.1245/s10434-007-9459-8 PubMedCrossRefGoogle Scholar
  28. 28.
    O’Connell P, Pekkel V, Fuqua SA, Osborne CK, Clark GM, Allred DC (1998) Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J Natl Cancer Inst 90:697–703. doi:10.1093/jnci/90.9.697 PubMedCrossRefGoogle Scholar
  29. 29.
    Aubele MM, Cummings MC, Mattis AE, Zitzelsberger HF, Walch AK, Kremer M et al (2000) Accumulation of chromosomal imbalances from intraductal proliferative lesions to adjacent in situ and invasive ductal breast cancer. Diagn Mol Pathol 9:14–19. doi:10.1097/00019606-200003000-00003 PubMedCrossRefGoogle Scholar
  30. 30.
    Ellsworth DL, Ellsworth RE, Love B, Deyarmin B, Lubert SM, Mittal V et al (2004) Genomic patterns of allelic imbalance in disease free tissue adjacent to primary breast carcinomas. Breast Cancer Res Treat 88:131–139. doi:10.1007/s10549-004-1424-7 PubMedCrossRefGoogle Scholar
  31. 31.
    Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS (1996) Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274:2057–2059. doi:10.1126/science.274.5295.2057 PubMedCrossRefGoogle Scholar
  32. 32.
    Forsti A, Louhelainen J, Soderberg M, Wijkstrom H, Hemminki K (2001) Loss of heterozygosity in tumour-adjacent normal tissue of breast and bladder cancer. Eur J Cancer 37:1372–1380. doi:10.1016/S0959-8049(01)00118-6 PubMedCrossRefGoogle Scholar
  33. 33.
    Euhus DM, Cler L, Shivapurkar N, Milchgrub S, Peters GN, Leitch AM et al (2002) Loss of heterozygosity in benign breast epithelium in relation to breast cancer risk. J Natl Cancer Inst 94:858–860PubMedGoogle Scholar
  34. 34.
    Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M, Tavassoli FA (2000) Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res 60:2562–2566PubMedGoogle Scholar
  35. 35.
    Ellsworth RE, Ellsworth DL, Lubert SM, Hooke J, Somiari RI, Shriver CD (2003) High-throughput loss of heterozygosity mapping in 26 commonly deleted regions in breast cancer. Cancer Epidemiol Biomarkers Prev 12:915–919PubMedGoogle Scholar
  36. 36.
    Ellsworth RE, Ellsworth DL, Deyarmin B, Hoffman LR, Love B, Hooke JA et al (2005) Timing of critical genetic changes in human breast disease. Ann Surg Oncol 12:1054–1060. doi:10.1245/ASO.2005.03.522 PubMedCrossRefGoogle Scholar
  37. 37.
    Baumgartner KB, Hunt WC, Baumgartner RN, Crumley DD, Gilliland FD, McTiernan A et al (2004) Association of body composition and weight history with breast cancer prognostic markers: divergent pattern for Hispanic and non-Hispanic White women. Am J Epidemiol 160:1087–1097. doi:10.1093/aje/kwh313 PubMedCrossRefGoogle Scholar
  38. 38.
    Bryant JE, Hutchings KG, Moyzis RK, Griffith JK (1997) Measurement of telomeric DNA content in human tissues. Biotechniques 23:476–478, 480, 482PubMedGoogle Scholar
  39. 39.
    Heaphy CM, Hines WC, Butler KS, Haaland CM, Heywood G, Fischer EG et al (2007) Assessment of the frequency of allelic imbalance in human tissue using a multiplex polymerase chain reaction system. J Mol Diagn 9:266–271. doi:10.2353/jmoldx.2007.060115 PubMedCrossRefGoogle Scholar
  40. 40.
    Hiyama E, Hiyama K (2002) Clinical utility of telomerase in cancer. Oncogene 21:643–649. doi:10.1038/sj.onc.1205070 PubMedCrossRefGoogle Scholar
  41. 41.
    Hines WC, Fajardo AM, Joste NE, Bisoffi M, Griffith JK (2005) Quantitative and spatial measurements of telomerase reverse transcriptase expression within normal and malignant human breast tissues. Mol Cancer Res 3:503–509. doi:10.1158/1541-7786.MCR-05-0031 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Christopher M. Heaphy
    • 1
  • Marco Bisoffi
    • 1
  • Nancy E. Joste
    • 2
  • Kathy B. Baumgartner
    • 3
    • 5
  • Richard N. Baumgartner
    • 4
    • 5
  • Jeffrey K. Griffith
    • 1
  1. 1.Department of Biochemistry and Molecular Biology, MSC08 46701 University of New MexicoAlbuquerqueUSA
  2. 2.Department of PathologyUniversity of New Mexico School of MedicineAlbuquerqueUSA
  3. 3.The New Mexico Tumor RegistryUniversity of New Mexico School of MedicineAlbuquerqueUSA
  4. 4.Department of Internal MedicineUniversity of New Mexico School of MedicineAlbuquerqueUSA
  5. 5.Department of Epidemiology and Clinical Investigation Science, School of Public Health and Information ScienceUniversity of LouisvilleLouisvilleUSA

Personalised recommendations