Skip to main content
Log in

Outer Breast Quadrants Demonstrate Increased Levels of Genomic Instability

  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background: Theory holds that the upper outer quadrant of the breast develops more malignancies because of increased tissue volume. This study evaluated genomic patterns of loss of heterozygosity (LOH) and allelic imbalance (AI) in non-neoplastic tissues from quadrants of diseased breasts following mastectomy to characterize relationships between genomic instability and the propensity for tumor development.

Methods: Tissues from breast quadrants were collected from 21 patients with various stages of breast carcinoma. DNA was isolated from non-neoplastic tissues using standard methods and 26 chromosomal regions commonly deleted in breast cancer were examined to assess genomic instability.

Results: Genomic instability was observed in breast quadrants from patients with ductal carcinomas in situ and advanced carcinomas. Levels of instability by quadrant were not predictive of primary tumor location (P = .363), but outer quadrants demonstrated significantly higher levels of genomic instability than did inner quadrants (P = .017). Marker D8S511 on chromosome 8p22– 21.3, one of the most frequently altered chromosomal regions in breast cancer, showed a significantly higher level of instability (P = .039) in outer compared with inner quadrants.

Conclusions: Non-neoplastic breast tissues often harbor genetic changes that can be important to understanding the local breast environment within which cancer develops. Greater genomic instability in outer quadrants can partially explain the propensity for breast cancers to develop there, rather than simple volume-related concepts. Patterns of field cancerization in the breast appear to be complex and are not a simple function of distance from a developing tumor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26.

    Article  PubMed  Google Scholar 

  2. Bevilacqua JLB, HS Cody III, MacDonald KA, Tan LK, Borgen PI, Van Zee KJ. A model for predicting axillary node metastases based on 2000 sentinel node procedures and tumour position. Eur J Surg Oncol 2002;28:490–500.

    PubMed  CAS  Google Scholar 

  3. Janni W, Rack B, Sommer H, et al. Intra-mammary tumor location does not influence prognosis but influences the prevalence of axillary lymph-node metastases. J Cancer Res Clin Oncol 2003;129:503–10.

    PubMed  Google Scholar 

  4. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919–32.

    Article  PubMed  CAS  Google Scholar 

  5. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998;396:643–9.

    Article  CAS  PubMed  Google Scholar 

  6. Washington C, Dalbègue F, Abreo F, Taubenberger JK, Lichy JH. Loss of heterozygosity in fibrocystic change of the breast: genetic relationship between benign proliferative lesions and associated carcinomas. Am J Pathol 2000;157:323–9.

    PubMed  CAS  Google Scholar 

  7. Kaneko M, Arihiro K, Takeshima Y, Fujii S, Inai K. Loss of heterozygosity and microsatellite instability in epithelial hyperplasia of the breast. J Exp Ther Oncol 2002;2:9–18.

    PubMed  CAS  Google Scholar 

  8. Tibiletti MG, Sessa F, Bernasconi B, et al. A large 6q deletion is a common cytogenetic alteration in fibroadenomas, pre-malignant lesions, and carcinomas of the breast. Clin Cancer Res 2000;6:1422–31.

    PubMed  CAS  Google Scholar 

  9. O’Connell P, Pekkel V, Fuqua SA, Osborne CK, Clark GM, Allred DC. Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J Natl Cancer Inst 1998;90:697–703.

    PubMed  CAS  Google Scholar 

  10. Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS. Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 1996;274:2057–9.

    PubMed  CAS  Google Scholar 

  11. Larson PS, de las Morenas A, Cupples LA, Huang K, Rosenberg CL. Genetically abnormal clones in histologically normal breast tissue. Am J Pathol 1998;152:1591–8.

    PubMed  CAS  Google Scholar 

  12. Moinfar F, Man YG, Bratthauer GL, Ratschek M, Tavassoli FA. Genetic abnormalities in mammary ductal intraepithelial neoplasia-flat type (“clinging ductal carcinoma in situ”): a simulator of normal mammary epithelium. Cancer 2000;88:2072–81.

    PubMed  CAS  Google Scholar 

  13. Försti A, Louhelainen J, Söderberg M, Wijkström H, Hemminki K. Loss of heterozygosity in tumour-adjacent normal tissue of breast and bladder cancer. Eur J Cancer 2001;37:1372–80.

    PubMed  Google Scholar 

  14. Kurose K, Hoshaw-Woodard S, Adeyinka A, Lemeshow S, Watson PH, Eng C. Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions. Hum Mol Genet 2001;10:1907–13.

    PubMed  CAS  Google Scholar 

  15. Wernert N, Locherbach C, Wellmann A, Behrens P, Hugel A. Presence of genetic alterations in microdissected stroma of human colon and breast cancers. Anticancer Res 2001;21:2259–64.

    PubMed  CAS  Google Scholar 

  16. Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou X-P, Eng C. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet 2002;32:355–7.

    PubMed  CAS  Google Scholar 

  17. Ellsworth DL, Shriver CD, Ellsworth RE, Deyarmin B, Somiari RI. Laser capture microdissection of paraffin-embedded tissues. Biotechniques 2003;34:42–6.

    PubMed  CAS  Google Scholar 

  18. American Joint Committee on Cancer. AJCC Cancer Staging Manual. 6th ed. New York: Springer, 2002.

  19. Millis RR, Hanby AM, Oberman HA. The breast. Sternberg SS, eds. Diagnostic Surgical Pathology 3rd ed, Lippincott, Williams & Wilkins: Philadelphia, 1999;319–85.

    Google Scholar 

  20. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991;19:403–10.

    CAS  PubMed  Google Scholar 

  21. Ellsworth RE, Ellsworth DL, Lubert SM, Hooke J, Somiari RI, Shriver CD. High-throughput loss of heterozygosity mapping in 26 commonly deleted regions in breast cancer. Cancer Epidemiol Biomarkers Prev 2003;12:915–9.

    PubMed  CAS  Google Scholar 

  22. Wang Y, Hung S-C, Linn JF, et al. Microsatellite-based cancer detection using capillary array electrophoresis and energy-transfer fluorescent primers. Electrophoresis 1997;18:1742–9.

    PubMed  CAS  Google Scholar 

  23. Medintz IL, Lee C-CR, Wong WW, Pirkola K, Sidransky D, Mathies RA. Loss of heterozygosity assay for molecular detection of cancer using energy-transfer primers and capillary array electrophoresis. Genome Res 2000;10:1211–8.

    PubMed  CAS  Google Scholar 

  24. Wild P, Knuechel R, Dietmaier W, Hofstaedter F, Hartmann A. Laser microdissection and microsatellite analyses of breast cancer reveal a high degree of tumor heterogeneity. Pathobiology 2000;68:180–90.

    PubMed  CAS  Google Scholar 

  25. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953;6:963–8.

    PubMed  CAS  Google Scholar 

  26. Tabor MP, Brakenhoff RH, van Houten VMM, et al. Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 2001;7:1523–32.

    PubMed  CAS  Google Scholar 

  27. Tabor MP, Brakenhoff RH, Ruijter-Schippers HJ, et al. Multiple head and neck tumors frequently originate from a single preneoplastic lesion. Am J Pathol 2002;161:1051–60.

    PubMed  CAS  Google Scholar 

  28. Franklin WA, Gazdar AF, Haney J, et al. Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis. J Clin Invest 1997;100:2133–7.

    Article  PubMed  CAS  Google Scholar 

  29. Prevo LJ, Sanchez CA, Galipeau PC, Reid BJ. p53-mutant clones and field effects in Barrett’s esophagus. Cancer Res 1999;59:4784–7.

    PubMed  CAS  Google Scholar 

  30. Chu T-Y, Shen C-Y, Lee H-S, Liu H-S. Monoclonality and surface lesion-specific microsatellite alterations in premalignant and malignant neoplasia of uterine cervix: a local field effect of genomic instability and clonal evolution. Genes Chromosomes Cancer 1999;24:127–34.

    PubMed  CAS  Google Scholar 

  31. Jothy S, Slesak B, Harlozinska A, Lapinska J, Adamiak J, Rabczynski J. Field effect of human colon carcinoma on normal mucosa: relevance of carcinoembryonic antigen expression. Tumour Biol 1996;17:58–64.

    Article  PubMed  CAS  Google Scholar 

  32. Braakhuis BJM, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 2003;63:1727–30.

    PubMed  CAS  Google Scholar 

  33. Kamel OW, Kempson RL, Hendrickson MR. In situ proliferative epithelial lesions of the breast. Pathology 1992;1:65–102.

    PubMed  CAS  Google Scholar 

  34. Estourgie SH, Nieweg OE, Valdés Olmos RA, Rutgers EJT, Kroon BBR. Lymphatic drainage patterns from the breast. Ann Surg 2004;239:232–7.

    PubMed  Google Scholar 

  35. Arbieva ZH, Banerjee K, Kim SY, et al. High-resolution physical map and transcript identification of a prostate cancer deletion interval on 8p22. Genome Res 2000;10:244–57.

    PubMed  CAS  Google Scholar 

  36. Bookstein R, Bova GS, MacGrogan D, Levy A, Isaacs WB. Tumour-suppressor genes in prostatic oncogenesis: a positional approach. Br J Urol. 1997;79(Suppl 1):28–36

    PubMed  Google Scholar 

  37. Kerangueven F, Noguchi T, Coulier F, et al. Genome-wide search for loss of heterozygosity shows extensive genetic diversity of human breast carcinomas. Cancer Res 1997;57:5469–74.

    PubMed  CAS  Google Scholar 

  38. Anbazhagan R, Fujii H, Gabrielson E. Allelic loss of chromosomal arm 8p in breast cancer progression. Am J Pathol 1998;152:815–9.

    PubMed  CAS  Google Scholar 

  39. Yuan B-Z, Zhou X, Durkin ME, et al. DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity. Oncogene 2003;22:445–50.

    PubMed  CAS  Google Scholar 

  40. Hamaguchi M, Meth JL, von Klitzing C, et al. DBC2, a candidate for a tumor suppressor gene involved in breast cancer. Proc Natl Acad Sci U S A 2002;99:13647–52.

    PubMed  CAS  Google Scholar 

  41. Zhou XZ, Lu KP. The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell 2001;107:347–59.

    Article  CAS  PubMed  Google Scholar 

  42. MacGrogan D, Levy A, Bova GS, Isaacs WB, Bookstein R. Structure and methylation-associated silencing of a gene within a homozygously deleted region of human chromosome band 8p22. Genomics 1996;35:55–65.

    Article  CAS  PubMed  Google Scholar 

  43. Cabeza-Arvelaiz Y, Sepulveda JL, Lebovitz RM, Thompson TC, Chinault AC. Functional identification of LZTS1 as a candidate prostate tumor suppressor gene on human chromosome 8p22. Oncogene 2001;20:4169–79.

    PubMed  CAS  Google Scholar 

  44. Fujiwara Y, Ohata H, Kuroki T, et al. Isolation of a candidate tumor suppressor gene on chromosome 8p21.3-p22 that is homologous to an extracellular domain of the PDGF receptor beta gene. Oncogene 1995;10:891–5.

    PubMed  CAS  Google Scholar 

  45. Karnik P, Paris M, Williams BRG, Casey G, Crowe J, Chen P. Two distinct tumor suppressor loci within chromosome 11p15 implicated in breast cancer progression and metastasis. Hum Mol Genet 1998;7:895–903.

    PubMed  CAS  Google Scholar 

  46. Minobe K, Onda M, Iida A, et al. Allelic loss on chromosome 9q is associated with lymph node metastasis of primary breast cancer. Jpn J Cancer Res 1998;89:916–22.

    PubMed  CAS  Google Scholar 

  47. Tsukamoto K, Ito N, Yoshimoto M, et al. Allelic loss on chromosome 1p is associated with progression and lymph node metastasis of primary breast carcinoma. Cancer 1998;82:317–22.

    PubMed  CAS  Google Scholar 

  48. Zucali R, Mariani L, Marubini E, et al. Early breast cancer: evaluation of the prognostic role of the site of the primary tumor. J Clin Oncol 1998;16:1363–6.

    PubMed  CAS  Google Scholar 

  49. Fredriksson I, Liljegren G, Arnesson L-G, et al. Local recurrence in the breast after conservative surgery–a study of prognosis and prognostic factors in 391 women. Eur J Cancer 2002;38:1860–70.

    PubMed  CAS  Google Scholar 

  50. Lininger RA, Fujii H, Man YG, Gabrielson E, Tavassoli FA. Comparison of loss of heterozygosity in primary and recurrent ductal carcinoma in situ of the breast. Mod Pathol 1998;11:1151–9.

    PubMed  CAS  Google Scholar 

  51. Regitnig P, Moser R, Thalhammer M, et al. Microsatellite analysis of breast carcinoma and corresponding local recurrences. J Pathol 2002;198:190–7.

    PubMed  CAS  Google Scholar 

  52. Partridge M, Pateromichelakis S, Phillips E, Emilion GG, A’Hern RP, Langdon JD. A case-control study confirms that microsatellite assay can identify patients at risk of developing oral squamous cell carcinoma within a field of cancerization. Cancer Res 2000;60:3893–8.

    PubMed  CAS  Google Scholar 

  53. Rosin MP, Cheng X, Poh C, et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 2000;6:357–62.

    PubMed  CAS  Google Scholar 

  54. Gupta D, Nath M, Layfield LJ. Utility of four-quadrant random sections in mastectomy specimens. Breast J 2003;9:307–11.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Darrell L. Ellsworth PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ellsworth, D.L., Ellsworth, R.E., Love, B. et al. Outer Breast Quadrants Demonstrate Increased Levels of Genomic Instability. Ann Surg Oncol 11, 861–868 (2004). https://doi.org/10.1245/ASO.2004.03.024

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1245/ASO.2004.03.024

Key Words

Navigation