Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 May;80(5-6):843–849. doi: 10.1038/sj.bjc.6690430

Frequent allelic losses at 11q24.1–q25 in young women with breast cancer: association with poor survival

M Gentile 1, K Olsen 2, M Dufmats 1, S Wingren 1
PMCID: PMC2362276  PMID: 10360664

Abstract

Previous studies have demonstrated that the pathological features of breast cancer are more aggressive in younger women than in their older counterparts, and that young age may be an independent marker for adverse prognosis. These findings have raised the question whether these differences are also present at the molecular level. In order to characterize the genetic alterations associated with early-onset breast cancer, 102 cases selected for age under 37 at diagnosis were examined for loss of heterozygosity (LOH) at nine different loci on chromosomes 11, 13 and 17. Ninety cases (88%), exhibited LOH for at least one marker. The D17S855 marker, intragenic in the BRCA1 gene, showed a high proportion of LOH (63%), whereas the intragenic marker for the TP53 gene, HP53, exhibited LOH in 43% of the cases. On chromosome 11, frequencies of LOH peaked at the D11S969 and D11S387 markers, which expressed LOH in 53% and 48% of the informative cases, whereas D11S1818, which is proximate to the ATM gene, exhibited an LOH frequency of 24%. A statistically significant correlation was found between LOH at the D11S387 marker and poor survival (P = 0.028). No such correlation was found for the adjacent D11S969 marker, located approximately 500 kb centromeric to D11S387. We conclude that one or more as yet unidentified genes, situated in chromosome bands 11q24.1–q25, could be involved in the initiation and/or progression of breast cancer in younger women. © 1999 Cancer Research Campaign

Keywords: early onset breast cancer, young age, poor prognosis, LOH analysis, 11q24.1–q25

Full Text

The Full Text of this article is available as a PDF (154.0 KB).

Selected References

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

  1. Adami H. O., Malker B., Holmberg L., Persson I., Stone B. The relation between survival and age at diagnosis in breast cancer. N Engl J Med. 1986 Aug 28;315(9):559–563. doi: 10.1056/NEJM198608283150906. [DOI] [PubMed] [Google Scholar]
  2. Albain K. S., Allred D. C., Clark G. M. Breast cancer outcome and predictors of outcome: are there age differentials? J Natl Cancer Inst Monogr. 1994;(16):35–42. [PubMed] [Google Scholar]
  3. Andersen T. I., Gaustad A., Ottestad L., Farrants G. W., Nesland J. M., Tveit K. M., Børresen A. L. Genetic alterations of the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q in human breast carcinomas. Genes Chromosomes Cancer. 1992 Mar;4(2):113–121. doi: 10.1002/gcc.2870040203. [DOI] [PubMed] [Google Scholar]
  4. Beckmann M. W., Picard F., An H. X., van Roeyen C. R., Dominik S. I., Mosny D. S., Schnürch H. G., Bender H. G., Niederacher D. Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer. Br J Cancer. 1996 May;73(10):1220–1226. doi: 10.1038/bjc.1996.234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bevilacqua G., Sobel M. E., Liotta L. A., Steeg P. S. Association of low nm23 RNA levels in human primary infiltrating ductal breast carcinomas with lymph node involvement and other histopathological indicators of high metastatic potential. Cancer Res. 1989 Sep 15;49(18):5185–5190. [PubMed] [Google Scholar]
  6. Bièche I., Noguès C., Rivoilan S., Khodja A., Latil A., Lidereau R. Prognostic value of loss of heterozygosity at BRCA2 in human breast carcinoma. Br J Cancer. 1997;76(11):1416–1418. doi: 10.1038/bjc.1997.572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bonnier P., Romain S., Charpin C., Lejeune C., Tubiana N., Martin P. M., Piana L. Age as a prognostic factor in breast cancer: relationship to pathologic and biologic features. Int J Cancer. 1995 Jul 17;62(2):138–144. doi: 10.1002/ijc.2910620205. [DOI] [PubMed] [Google Scholar]
  8. Borg A., Zhang Q. X., Alm P., Olsson H., Sellberg G. The retinoblastoma gene in breast cancer: allele loss is not correlated with loss of gene protein expression. Cancer Res. 1992 May 15;52(10):2991–2994. [PubMed] [Google Scholar]
  9. Caleffi M., Teague M. W., Jensen R. A., Vnencak-Jones C. L., Dupont W. D., Parl F. F. p53 gene mutations and steroid receptor status in breast cancer. Clinicopathologic correlations and prognostic assessment. Cancer. 1994 Apr 15;73(8):2147–2156. doi: 10.1002/1097-0142(19940415)73:8<2147::aid-cncr2820730820>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  10. Chung M., Chang H. R., Bland K. I., Wanebo H. J. Younger women with breast carcinoma have a poorer prognosis than older women. Cancer. 1996 Jan 1;77(1):97–103. doi: 10.1002/(SICI)1097-0142(19960101)77:1<97::AID-CNCR16>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Devilee P., van Vliet M., Bardoel A., Kievits T., Kuipers-Dijkshoorn N., Pearson P. L., Cornelisse C. J. Frequent somatic imbalance of marker alleles for chromosome 1 in human primary breast carcinoma. Cancer Res. 1991 Feb 1;51(3):1020–1025. [PubMed] [Google Scholar]
  13. Easton D. F. Cancer risks in A-T heterozygotes. Int J Radiat Biol. 1994 Dec;66(6 Suppl):S177–S182. doi: 10.1080/09553009414552011. [DOI] [PubMed] [Google Scholar]
  14. Easton D. F., Ford D., Bishop D. T. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995 Jan;56(1):265–271. [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. FitzGerald M. G., Bean J. M., Hegde S. R., Unsal H., MacDonald D. J., Harkin D. P., Finkelstein D. M., Isselbacher K. J., Haber D. A. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet. 1997 Mar;15(3):307–310. doi: 10.1038/ng0397-307. [DOI] [PubMed] [Google Scholar]
  17. Futreal P. A., Liu Q., Shattuck-Eidens D., Cochran C., Harshman K., Tavtigian S., Bennett L. M., Haugen-Strano A., Swensen J., Miki Y. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994 Oct 7;266(5182):120–122. doi: 10.1126/science.7939630. [DOI] [PubMed] [Google Scholar]
  18. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994 Sep 15;54(18):4855–4878. [PubMed] [Google Scholar]
  19. Gudmundsson J., Barkardottir R. B., Eiriksdottir G., Baldursson T., Arason A., Egilsson V., Ingvarsson S. Loss of heterozygosity at chromosome 11 in breast cancer: association of prognostic factors with genetic alterations. Br J Cancer. 1995 Sep;72(3):696–701. doi: 10.1038/bjc.1995.396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hennessy C., Henry J. A., May F. E., Westley B. R., Angus B., Lennard T. W. Expression of the antimetastatic gene nm23 in human breast cancer: an association with good prognosis. J Natl Cancer Inst. 1991 Feb 20;83(4):281–285. doi: 10.1093/jnci/83.4.281. [DOI] [PubMed] [Google Scholar]
  21. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  22. Høst H., Lund E. Age as a prognostic factor in breast cancer. Cancer. 1986 Jun 1;57(11):2217–2221. doi: 10.1002/1097-0142(19860601)57:11<2217::aid-cncr2820571124>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
  23. Jensen D. E., Proctor M., Marquis S. T., Gardner H. P., Ha S. I., Chodosh L. A., Ishov A. M., Tommerup N., Vissing H., Sekido Y. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene. 1998 Mar 5;16(9):1097–1112. doi: 10.1038/sj.onc.1201861. [DOI] [PubMed] [Google Scholar]
  24. Kerangueven F., Allione F., Noguchi T., Adélaïde J., Sobol H., Jacquemier J., Birnbaum D. Patterns of loss of heterozygosity at loci from chromosome arm 13q suggests a possible involvement of BRCA2 in sporadic breast tumors. Genes Chromosomes Cancer. 1995 Aug;13(4):291–294. doi: 10.1002/gcc.2870130410. [DOI] [PubMed] [Google Scholar]
  25. Kerangueven F., Eisinger F., Noguchi T., Allione F., Wargniez V., Eng C., Padberg G., Theillet C., Jacquemier J., Longy M. Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions. Oncogene. 1997 Jan 23;14(3):339–347. doi: 10.1038/sj.onc.1200818. [DOI] [PubMed] [Google Scholar]
  26. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Koreth J., Bakkenist C. J., McGee J. O. Allelic deletions at chromosome 11q22-q23.1 and 11q25-qterm are frequent in sporadic breast but not colorectal cancers. Oncogene. 1997 Jan 30;14(4):431–437. doi: 10.1038/sj.onc.1200847. [DOI] [PubMed] [Google Scholar]
  28. Krainer M., Silva-Arrieta S., FitzGerald M. G., Shimada A., Ishioka C., Kanamaru R., MacDonald D. J., Unsal H., Finkelstein D. M., Bowcock A. Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer. N Engl J Med. 1997 May 15;336(20):1416–1421. doi: 10.1056/NEJM199705153362003. [DOI] [PubMed] [Google Scholar]
  29. Leone A., Flatow U., King C. R., Sandeen M. A., Margulies I. M., Liotta L. A., Steeg P. S. Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell. 1991 Apr 5;65(1):25–35. doi: 10.1016/0092-8674(91)90404-m. [DOI] [PubMed] [Google Scholar]
  30. Leone A., Flatow U., VanHoutte K., Steeg P. S. Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: effects on tumor metastatic potential, colonization and enzymatic activity. Oncogene. 1993 Sep;8(9):2325–2333. [PubMed] [Google Scholar]
  31. Lizard-Nacol S., Riedinger J. M., Lizard G., Glasser A. L., Coudray N., Chaplain G., Guerrin J. Loss of heterozygosity at the TP53 gene: independent occurrence from genetic instability events in node-negative breast cancer. Int J Cancer. 1997 Aug 7;72(4):599–603. doi: 10.1002/(sici)1097-0215(19970807)72:4<599::aid-ijc8>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  32. Marcus J. N., Watson P., Page D. L., Lynch H. T. Pathology and heredity of breast cancer in younger women. J Natl Cancer Inst Monogr. 1994;(16):23–34. [PubMed] [Google Scholar]
  33. Merajver S. D., Pham T. M., Caduff R. F., Chen M., Poy E. L., Cooney K. A., Weber B. L., Collins F. S., Johnston C., Frank T. S. Somatic mutations in the BRCA1 gene in sporadic ovarian tumours. Nat Genet. 1995 Apr;9(4):439–443. doi: 10.1038/ng0495-439. [DOI] [PubMed] [Google Scholar]
  34. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P. A., Harshman K., Tavtigian S., Liu Q., Cochran C., Bennett L. M., Ding W. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66–71. doi: 10.1126/science.7545954. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Nagai M. A., Pacheco M. M., Brentani M. M., Marques L. A., Brentani R. R., Ponder B. A., Mulligan L. M. Allelic loss on distal chromosome 17p is associated with poor prognosis in a group of Brazilian breast cancer patients. Br J Cancer. 1994 Apr;69(4):754–758. doi: 10.1038/bjc.1994.142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Niederacher D., Picard F., van Roeyen C., An H. X., Bender H. G., Beckmann M. W. Patterns of allelic loss on chromosome 17 in sporadic breast carcinomas detected by fluorescent-labeled microsatellite analysis. Genes Chromosomes Cancer. 1997 Mar;18(3):181–192. doi: 10.1002/(sici)1098-2264(199703)18:3<181::aid-gcc5>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  38. Nigro J. M., Baker S. J., Preisinger A. C., Jessup J. M., Hostetter R., Cleary K., Bigner S. H., Davidson N., Baylin S., Devilee P. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989 Dec 7;342(6250):705–708. doi: 10.1038/342705a0. [DOI] [PubMed] [Google Scholar]
  39. Phelan C. M., Lancaster J. M., Tonin P., Gumbs C., Cochran C., Carter R., Ghadirian P., Perret C., Moslehi R., Dion F. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet. 1996 May;13(1):120–122. doi: 10.1038/ng0596-120. [DOI] [PubMed] [Google Scholar]
  40. Sanford K. K., Parshad R., Price F. M., Jones G. M., Tarone R. E., Eierman L., Hale P., Waldmann T. A. Enhanced chromatid damage in blood lymphocytes after G2 phase x irradiation, a marker of the ataxia-telangiectasia gene. J Natl Cancer Inst. 1990 Jun 20;82(12):1050–1054. doi: 10.1093/jnci/82.12.1050. [DOI] [PubMed] [Google Scholar]
  41. Savitsky K., Bar-Shira A., Gilad S., Rotman G., Ziv Y., Vanagaite L., Tagle D. A., Smith S., Uziel T., Sfez S. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995 Jun 23;268(5218):1749–1753. doi: 10.1126/science.7792600. [DOI] [PubMed] [Google Scholar]
  42. Schmutzler R. K., Fimmers R., Bierhoff E., Lohmar B., Homann A., Speiser P., Kubista E., Jaeger K., Krebs D., Zeillinger R. Association of allelic losses on human chromosomal arms 11Q and 16Q in sporadic breast cancer. Int J Cancer. 1996 Aug 22;69(4):307–311. doi: 10.1002/(SICI)1097-0215(19960822)69:4<307::AID-IJC12>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  43. Scully R., Chen J., Plug A., Xiao Y., Weaver D., Feunteun J., Ashley T., Livingston D. M. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell. 1997 Jan 24;88(2):265–275. doi: 10.1016/s0092-8674(00)81847-4. [DOI] [PubMed] [Google Scholar]
  44. Sherr C. J. Cancer cell cycles. Science. 1996 Dec 6;274(5293):1672–1677. doi: 10.1126/science.274.5293.1672. [DOI] [PubMed] [Google Scholar]
  45. Shibata D., Brynes R. K., Nathwani B., Kwok S., Sninsky J., Arnheim N. Human immunodeficiency viral DNA is readily found in lymph node biopsies from seropositive individuals. Analysis of fixed tissue using the polymerase chain reaction. Am J Pathol. 1989 Oct;135(4):697–702. [PMC free article] [PubMed] [Google Scholar]
  46. Sourvinos G., Spandidos D. A. Decreased BRCA1 expression levels may arrest the cell cycle through activation of p53 checkpoint in human sporadic breast tumors. Biochem Biophys Res Commun. 1998 Apr 7;245(1):75–80. doi: 10.1006/bbrc.1998.8379. [DOI] [PubMed] [Google Scholar]
  47. Stürzbecher H. W., Donzelmann B., Henning W., Knippschild U., Buchhop S. p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction. EMBO J. 1996 Apr 15;15(8):1992–2002. [PMC free article] [PubMed] [Google Scholar]
  48. Swift M. Ionizing radiation, breast cancer, and ataxia-telangiectasia. J Natl Cancer Inst. 1994 Nov 2;86(21):1571–1572. doi: 10.1093/jnci/86.21.1571. [DOI] [PubMed] [Google Scholar]
  49. Swift M., Morrell D., Massey R. B., Chase C. L. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med. 1991 Dec 26;325(26):1831–1836. doi: 10.1056/NEJM199112263252602. [DOI] [PubMed] [Google Scholar]
  50. Swift M., Reitnauer P. J., Morrell D., Chase C. L. Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med. 1987 May 21;316(21):1289–1294. doi: 10.1056/NEJM198705213162101. [DOI] [PubMed] [Google Scholar]
  51. Szabo C. I., King M. C. Inherited breast and ovarian cancer. Hum Mol Genet. 1995;4(Spec No):1811–1817. doi: 10.1093/hmg/4.suppl_1.1811. [DOI] [PubMed] [Google Scholar]
  52. Tavtigian S. V., Simard J., Rommens J., Couch F., Shattuck-Eidens D., Neuhausen S., Merajver S., Thorlacius S., Offit K., Stoppa-Lyonnet D. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996 Mar;12(3):333–337. doi: 10.1038/ng0396-333. [DOI] [PubMed] [Google Scholar]
  53. Vaughn J. P., Cirisano F. D., Huper G., Berchuck A., Futreal P. A., Marks J. R., Iglehart J. D. Cell cycle control of BRCA2. Cancer Res. 1996 Oct 15;56(20):4590–4594. [PubMed] [Google Scholar]
  54. Vorechovský I., Luo L., Lindblom A., Negrini M., Webster A. D., Croce C. M., Hammarström L. ATM mutations in cancer families. Cancer Res. 1996 Sep 15;56(18):4130–4133. [PubMed] [Google Scholar]
  55. Vorechovský I., Rasio D., Luo L., Monaco C., Hammarström L., Webster A. D., Zaloudik J., Barbanti-Brodani G., James M., Russo G. The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation. Cancer Res. 1996 Jun 15;56(12):2726–2732. [PubMed] [Google Scholar]
  56. Walker R. A., Lees E., Webb M. B., Dearing S. J. Breast carcinomas occurring in young women (< 35 years) are different. Br J Cancer. 1996 Dec;74(11):1796–1800. doi: 10.1038/bjc.1996.632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Wenger C. R., Beardslee S., Owens M. A., Pounds G., Oldaker T., Vendely P., Pandian M. R., Harrington D., Clark G. M., McGuire W. L. DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients. Breast Cancer Res Treat. 1993 Oct;28(1):9–20. doi: 10.1007/BF00666351. [DOI] [PubMed] [Google Scholar]
  58. Westphal C. H., Rowan S., Schmaltz C., Elson A., Fisher D. E., Leder P. atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nat Genet. 1997 Aug;16(4):397–401. doi: 10.1038/ng0897-397. [DOI] [PubMed] [Google Scholar]
  59. Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J., Collins N., Gregory S., Gumbs C., Micklem G. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21;378(6559):789–792. doi: 10.1038/378789a0. [DOI] [PubMed] [Google Scholar]
  60. de la Rochefordiere A., Asselain B., Campana F., Scholl S. M., Fenton J., Vilcoq J. R., Durand J. C., Pouillart P., Magdelenat H., Fourquet A. Age as prognostic factor in premenopausal breast carcinoma. Lancet. 1993 Apr 24;341(8852):1039–1043. doi: 10.1016/0140-6736(93)92407-k. [DOI] [PubMed] [Google Scholar]

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

RESOURCES