Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1998 Mar;77(5):797–800. doi: 10.1038/bjc.1998.129

Allelic imbalance at chromosome 17p13.3 (YNZ22) in breast cancer is independent of p53 mutation or p53 overexpression and is associated with poor prognosis at medium-term follow-up.

A M Thompson 1, D N Crichton 1, R A Elton 1, M F Clay 1, U Chetty 1, C M Steel 1
PMCID: PMC2149971  PMID: 9514060

Abstract

Molecular and immunohistochemical studies of genetic events on chromosome 17p were prospectively compared with conventional clinical and pathological parameters and disease behaviour at a minimum of 72 months follow-up. In a series of 91 patients with primary operable breast cancer, 37 out of 91 (41%) patients had disease relapse and 23 out of 91 (25%) had died during the follow-up period. Allelic imbalance at the YNZ22 locus (17p13.3), demonstrated in 33 out of 63 (52%) informative patients, was significantly associated with disease recurrence (P < 0.01, 2 d.f. Cox analysis) and showed a trend towards impaired survival (P = 0.08, 2 d.f. Cox analysis) after a mean follow-up of 84 months for survivors. By contrast, p53 mutation (in 10 out of 60, 17% of cancers), p53 allelic imbalance (in 23 out of 56, 41% informative patients), p53 mRNA expression (in 47 out of 87, 54% patients), p53 mRNA overexpression (in 24 out of 87, 28%) or p53 protein expression (detected in 25/76, 32%) were not associated with disease behaviour. There was no significant association between allelic imbalance at YNZ22 and any abnormality of p53 DNA, RNA or protein. Allelic imbalance at 17p13.3 (YNZ22) serves as a marker of poor prognosis in breast cancer. As yet unidentified genes on 17p13.3, distinct from and telomeric to p53, are therefore likely to be of clinical importance in breast cancer.

Full text

PDF
797

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aas T., Børresen A. L., Geisler S., Smith-Sørensen B., Johnsen H., Varhaug J. E., Akslen L. A., Lønning P. E. Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med. 1996 Jul;2(7):811–814. doi: 10.1038/nm0796-811. [DOI] [PubMed] [Google Scholar]
  2. Allred D. C., Clark G. M., Elledge R., Fuqua S. A., Brown R. W., Chamness G. C., Osborne C. K., McGuire W. L. Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst. 1993 Feb 3;85(3):200–206. doi: 10.1093/jnci/85.3.200. [DOI] [PubMed] [Google Scholar]
  3. Andersen T. I., Holm R., Nesland J. M., Heimdal K. R., Ottestad L., Børresen A. L. Prognostic significance of TP53 alterations in breast carcinoma. Br J Cancer. 1993 Sep;68(3):540–548. doi: 10.1038/bjc.1993.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barnes D. M., Dublin E. A., Fisher C. J., Levison D. A., Millis R. R. Immunohistochemical detection of p53 protein in mammary carcinoma: an important new independent indicator of prognosis? Hum Pathol. 1993 May;24(5):469–476. doi: 10.1016/0046-8177(93)90158-d. [DOI] [PubMed] [Google Scholar]
  5. Bergh J., Norberg T., Sjögren S., Lindgren A., Holmberg L. Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nat Med. 1995 Oct;1(10):1029–1034. doi: 10.1038/nm1095-1029. [DOI] [PubMed] [Google Scholar]
  6. Bland K. I., Konstadoulakis M. M., Vezeridis M. P., Wanebo H. J. Oncogene protein co-expression. Value of Ha-ras, c-myc, c-fos, and p53 as prognostic discriminants for breast carcinoma. Ann Surg. 1995 Jun;221(6):706–720. doi: 10.1097/00000658-199506000-00010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Borg A., Lennerstrand J., Stenmark-Askmalm M., Fernö M., Brisfors A., Ohrvik A., Stål O., Killander D., Lane D., Brundell J. Prognostic significance of p53 overexpression in primary breast cancer; a novel luminometric immunoassay applicable on steroid receptor cytosols. Br J Cancer. 1995 May;71(5):1013–1017. doi: 10.1038/bjc.1995.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Børresen A. L., Andersen T. I., Eyfjörd J. E., Cornelis R. S., Thorlacius S., Borg A., Johansson U., Theillet C., Scherneck S., Hartman S. TP53 mutations and breast cancer prognosis: particularly poor survival rates for cases with mutations in the zinc-binding domains. Genes Chromosomes Cancer. 1995 Sep;14(1):71–75. doi: 10.1002/gcc.2870140113. [DOI] [PubMed] [Google Scholar]
  9. Cattoretti G., Rilke F., Andreola S., D'Amato L., Delia D. P53 expression in breast cancer. Int J Cancer. 1988 Feb 15;41(2):178–183. doi: 10.1002/ijc.2910410204. [DOI] [PubMed] [Google Scholar]
  10. Chen L. C., Neubauer A., Kurisu W., Waldman F. M., Ljung B. M., Goodson W., 3rd, Goldman E. S., Moore D., 2nd, Balazs M., Liu E. Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3847–3851. doi: 10.1073/pnas.88.9.3847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chen T., Dhingra K., Sahin A., Sneige N., Hortobagyi G., Aldaz C. M. Technical approach for the study of the genetic evolution of breast cancer from paraffin-embedded tissue sections. Breast Cancer Res Treat. 1996;39(2):177–185. doi: 10.1007/BF01806184. [DOI] [PubMed] [Google Scholar]
  12. Coles C., Thompson A. M., Elder P. A., Cohen B. B., Mackenzie I. M., Cranston G., Chetty U., Mackay J., Macdonald M., Nakamura Y. Evidence implicating at least two genes on chromosome 17p in breast carcinogenesis. Lancet. 1990 Sep 29;336(8718):761–763. doi: 10.1016/0140-6736(90)93236-i. [DOI] [PubMed] [Google Scholar]
  13. Cornelis R. S., van Vliet M., Vos C. B., Cleton-Jansen A. M., van de Vijver M. J., Peterse J. L., Khan P. M., Børresen A. L., Cornelisse C. J., Devilee P. Evidence for a gene on 17p13.3, distal to TP53, as a target for allele loss in breast tumors without p53 mutations. Cancer Res. 1994 Aug 1;54(15):4200–4206. [PubMed] [Google Scholar]
  14. Davidoff A. M., Herndon J. E., 2nd, Glover N. S., Kerns B. J., Pence J. C., Iglehart J. D., Marks J. R. Relation between p53 overexpression and established prognostic factors in breast cancer. Surgery. 1991 Aug;110(2):259–264. [PubMed] [Google Scholar]
  15. Devilee P., van den Broek M., Kuipers-Dijkshoorn N., Kolluri R., Khan P. M., Pearson P. L., Cornelisse C. J. At least four different chromosomal regions are involved in loss of heterozygosity in human breast carcinoma. Genomics. 1989 Oct;5(3):554–560. doi: 10.1016/0888-7543(89)90023-2. [DOI] [PubMed] [Google Scholar]
  16. Elledge R. M., Allred D. C. The p53 tumor suppressor gene in breast cancer. Breast Cancer Res Treat. 1994;32(1):39–47. doi: 10.1007/BF00666204. [DOI] [PubMed] [Google Scholar]
  17. Elledge R. M., Clark G. M., Fuqua S. A., Yu Y. Y., Allred D. C. p53 protein accumulation detected by five different antibodies: relationship to prognosis and heat shock protein 70 in breast cancer. Cancer Res. 1994 Jul 15;54(14):3752–3757. [PubMed] [Google Scholar]
  18. Elledge R. M., Gray R., Mansour E., Yu Y., Clark G. M., Ravdin P., Osborne C. K., Gilchrist K., Davidson N. E., Robert N. Accumulation of p53 protein as a possible predictor of response to adjuvant combination chemotherapy with cyclophosphamide, methotrexate, fluorouracil, and prednisone for breast cancer. J Natl Cancer Inst. 1995 Aug 16;87(16):1254–1256. doi: 10.1093/jnci/87.16.1254. [DOI] [PubMed] [Google Scholar]
  19. Friedrichs K., Gluba S., Eidtmann H., Jonat W. Overexpression of p53 and prognosis in breast cancer. Cancer. 1993 Dec 15;72(12):3641–3647. doi: 10.1002/1097-0142(19931215)72:12<3641::aid-cncr2820721215>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  20. Harada Y., Katagiri T., Ito I., Akiyama F., Sakamoto G., Kasumi F., Nakamura Y., Emi M. Genetic studies of 457 breast cancers. Clinicopathologic parameters compared with genetic alterations. Cancer. 1994 Oct 15;74(8):2281–2286. doi: 10.1002/1097-0142(19941015)74:8<2281::aid-cncr2820740812>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  21. Heisterkamp N., Morris C., Groffen J. ABR, an active BCR-related gene. Nucleic Acids Res. 1989 Nov 11;17(21):8821–8831. doi: 10.1093/nar/17.21.8821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Isola J., Visakorpi T., Holli K., Kallioniemi O. P. Association of overexpression of tumor suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients. J Natl Cancer Inst. 1992 Jul 15;84(14):1109–1114. doi: 10.1093/jnci/84.14.1109. [DOI] [PubMed] [Google Scholar]
  23. Ito I., Yoshimoto M., Iwase T., Watanabe S., Katagiri T., Harada Y., Kasumi F., Yasuda S., Mitomi T., Emi M. Association of genetic alterations on chromosome 17 and loss of hormone receptors in breast cancer. Br J Cancer. 1995 Mar;71(3):438–441. doi: 10.1038/bjc.1995.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Iwaya K., Tsuda H., Hiraide H., Tamaki K., Tamakuma S., Fukutomi T., Mukai K., Hirohashi S. Nuclear p53 immunoreaction associated with poor prognosis of breast cancer. Jpn J Cancer Res. 1991 Jul;82(7):835–840. doi: 10.1111/j.1349-7006.1991.tb02710.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kovach J. S., McGovern R. M., Cassady J. D., Swanson S. K., Wold L. E., Vogelstein B., Sommer S. S. Direct sequencing from touch preparations of human carcinomas: analysis of p53 mutations in breast carcinomas. J Natl Cancer Inst. 1991 Jul 17;83(14):1004–1009. doi: 10.1093/jnci/83.14.1004. [DOI] [PubMed] [Google Scholar]
  26. Lakhani S. R., Collins N., Stratton M. R., Sloane J. P. Atypical ductal hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p. J Clin Pathol. 1995 Jul;48(7):611–615. doi: 10.1136/jcp.48.7.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. MacGrogan G., Bonichon F., de Mascarel I., Trojani M., Durand M., Avril A., Coindre J. M. Prognostic value of p53 in breast invasive ductal carcinoma: an immunohistochemical study on 942 cases. Breast Cancer Res Treat. 1995;36(1):71–81. doi: 10.1007/BF00690187. [DOI] [PubMed] [Google Scholar]
  28. Mackay J., Steel C. M., Elder P. A., Forrest A. P., Evans H. J. Allele loss on short arm of chromosome 17 in breast cancers. Lancet. 1988 Dec 17;2(8625):1384–1385. doi: 10.1016/s0140-6736(88)90584-3. [DOI] [PubMed] [Google Scholar]
  29. Marks J. R., Humphrey P. A., Wu K., Berry D., Bandarenko N., Kerns B. J., Iglehart J. D. Overexpression of p53 and HER-2/neu proteins as prognostic markers in early stage breast cancer. Ann Surg. 1994 Apr;219(4):332–341. doi: 10.1097/00000658-199404000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Martinazzi M., Crivelli F., Zampatti C., Martinazzi S. Relationship between p53 expression and other prognostic factors in human breast carcinoma. An immunohistochemical study. Am J Clin Pathol. 1993 Sep;100(3):213–217. doi: 10.1093/ajcp/100.3.213. [DOI] [PubMed] [Google Scholar]
  31. Merlo G. R., Venesio T., Bernardi A., Canale L., Gaglia P., Lauro D., Cappa A. P., Callahan R., Liscia D. S. Loss of heterozygosity on chromosome 17p13 in breast carcinomas identifies tumors with high proliferation index. Am J Pathol. 1992 Jan;140(1):215–223. [PMC free article] [PubMed] [Google Scholar]
  32. Morris C., Benjes S., Haataja L., Ledbetter D. H., Heisterkamp N., Groffen J. Spatial organization of ABR and CRK genes on human chromosome band 17p13.3. Oncogene. 1995 Mar 2;10(5):1009–1011. [PubMed] [Google Scholar]
  33. Munn K. E., Walker R. A., Menasce L., Varley J. M. Mutation of the TP53 gene and allelic imbalance at chromosome 17p13 in ductal carcinoma in situ. Br J Cancer. 1996 Nov;74(10):1578–1585. doi: 10.1038/bjc.1996.592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nagai M. A., Medeiros A. C., Brentani M. M., Brentani R. R., Marques L. A., Mazoyer S., Mulligan L. M. Five distinct deleted regions on chromosome 17 defining different subsets of human primary breast tumors. Oncology. 1995 Nov-Dec;52(6):448–453. doi: 10.1159/000227509. [DOI] [PubMed] [Google Scholar]
  35. Osborne R. J., Merlo G. R., Mitsudomi T., Venesio T., Liscia D. S., Cappa A. P., Chiba I., Takahashi T., Nau M. M., Callahan R. Mutations in the p53 gene in primary human breast cancers. Cancer Res. 1991 Nov 15;51(22):6194–6198. [PubMed] [Google Scholar]
  36. Poller D. N., Hutchings C. E., Galea M., Bell J. A., Nicholson R. A., Elston C. W., Blamey R. W., Ellis I. O. p53 protein expression in human breast carcinoma: relationship to expression of epidermal growth factor receptor, c-erbB-2 protein overexpression, and oestrogen receptor. Br J Cancer. 1992 Sep;66(3):583–588. doi: 10.1038/bjc.1992.318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Prosser J., Thompson A. M., Cranston G., Evans H. J. Evidence that p53 behaves as a tumour suppressor gene in sporadic breast tumours. Oncogene. 1990 Oct;5(10):1573–1579. [PubMed] [Google Scholar]
  38. Radford D. M., Fair K., Thompson A. M., Ritter J. H., Holt M., Steinbrueck T., Wallace M., Wells S. A., Jr, Donis-Keller H. R. Allelic loss on a chromosome 17 in ductal carcinoma in situ of the breast. Cancer Res. 1993 Jul 1;53(13):2947–2949. [PubMed] [Google Scholar]
  39. Runnebaum I. B., Nagarajan M., Bowman M., Soto D., Sukumar S. Mutations in p53 as potential molecular markers for human breast cancer. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10657–10661. doi: 10.1073/pnas.88.23.10657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Silvestrini R., Benini E., Daidone M. G., Veneroni S., Boracchi P., Cappelletti V., Di Fronzo G., Veronesi U. p53 as an independent prognostic marker in lymph node-negative breast cancer patients. J Natl Cancer Inst. 1993 Jun 16;85(12):965–970. doi: 10.1093/jnci/85.12.965. [DOI] [PubMed] [Google Scholar]
  41. Silvestrini R., Daidone M. G., Benini E., Faranda A., Tomasic G., Boracchi P., Salvadori B., Veronesi U. Validation of p53 accumulation as a predictor of distant metastasis at 10 years of follow-up in 1400 node-negative breast cancers. Clin Cancer Res. 1996 Dec;2(12):2007–2013. [PubMed] [Google Scholar]
  42. Singh S., Simon M., Meybohm I., Jantke I., Jonat W., Maass H., Goedde H. W. Human breast cancer: frequent p53 allele loss and protein overexpression. Hum Genet. 1993 Feb;90(6):635–640. doi: 10.1007/BF00202481. [DOI] [PubMed] [Google Scholar]
  43. Stack M., Jones D., White G., Liscia D. S., Venesio T., Casey G., Crichton D., Varley J., Mitchell E., Heighway J. Detailed mapping and loss of heterozygosity analysis suggests a suppressor locus involved in sporadic breast cancer within a distal region of chromosome band 17p13.3. Hum Mol Genet. 1995 Nov;4(11):2047–2055. doi: 10.1093/hmg/4.11.2047. [DOI] [PubMed] [Google Scholar]
  44. Stenmark-Askmalm M., Stål O., Olsen K., Nordenskjöld B. p53 as a prognostic factor in stage I breast cancer. South-East Sweden Breast Cancer Group. Br J Cancer. 1995 Sep;72(3):715–719. doi: 10.1038/bjc.1995.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Takita K., Sato T., Miyagi M., Watatani M., Akiyama F., Sakamoto G., Kasumi F., Abe R., Nakamura Y. Correlation of loss of alleles on the short arms of chromosomes 11 and 17 with metastasis of primary breast cancer to lymph nodes. Cancer Res. 1992 Jul 15;52(14):3914–3917. [PubMed] [Google Scholar]
  46. Thompson A. M., Anderson T. J., Condie A., Prosser J., Chetty U., Carter D. C., Evans H. J., Steel C. M. p53 allele losses, mutations and expression in breast cancer and their relationship to clinico-pathological parameters. Int J Cancer. 1992 Feb 20;50(4):528–532. doi: 10.1002/ijc.2910500405. [DOI] [PubMed] [Google Scholar]
  47. Thompson A. M., Steel C. M., Chetty U., Hawkins R. A., Miller W. R., Carter D. C., Forrest A. P., Evans H. J. p53 gene mRNA expression and chromosome 17p allele loss in breast cancer. Br J Cancer. 1990 Jan;61(1):74–78. doi: 10.1038/bjc.1990.17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Thorlacius S., Börresen A. L., Eyfjörd J. E. Somatic p53 mutations in human breast carcinomas in an Icelandic population: a prognostic factor. Cancer Res. 1993 Apr 1;53(7):1637–1641. [PubMed] [Google Scholar]
  49. Tsuda H., Iwaya K., Fukutomi T., Hirohashi S. p53 mutations and c-erbB-2 amplification in intraductal and invasive breast carcinomas of high histologic grade. Jpn J Cancer Res. 1993 Apr;84(4):394–401. doi: 10.1111/j.1349-7006.1993.tb00149.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Varley J. M., Brammar W. J., Lane D. P., Swallow J. E., Dolan C., Walker R. A. Loss of chromosome 17p13 sequences and mutation of p53 in human breast carcinomas. Oncogene. 1991 Mar;6(3):413–421. [PubMed] [Google Scholar]
  51. Vojtesek B., Bártek J., Midgley C. A., Lane D. P. An immunochemical analysis of the human nuclear phosphoprotein p53. New monoclonal antibodies and epitope mapping using recombinant p53. J Immunol Methods. 1992 Jul 6;151(1-2):237–244. doi: 10.1016/0022-1759(92)90122-a. [DOI] [PubMed] [Google Scholar]
  52. Wales M. M., Biel M. A., el Deiry W., Nelkin B. D., Issa J. P., Cavenee W. K., Kuerbitz S. J., Baylin S. B. p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nat Med. 1995 Jun;1(6):570–577. doi: 10.1038/nm0695-570. [DOI] [PubMed] [Google Scholar]
  53. White G. R., Stack M., Santibáez-Koref M., Liscia D. S., Venesio T., Wang J. C., Helms C., Donis-Keller H., Betticher D. C., Altermatt H. J. High levels of loss at the 17p telomere suggest the close proximity of a tumour suppressor. Br J Cancer. 1996 Sep;74(6):863–870. doi: 10.1038/bjc.1996.449. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES