Skip to main content
SpringerLink
Log in

Loss of Heterozygosity in Bilateral Breast Cancer

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Women who develop bilateral breast cancer at an early age are likely to harbour germline mutations in breast cancer susceptibility genes. The aim of this study was to test for concordant genetic changes in left and right breast cancer of young women (age <50) with bilateral breast cancer that may suggest an inherited breast cancer predisposition. Microsatellite markers were used to test for loss of heterozygosity (LOH) in left and right tumours for 31 women with premenopausal bilateral breast cancer. Markers adjacent to or within candidate genes on 17p (p53), 17q (BRCA1), 13q (BRCA2), 11q (Ataxia Telangiectasia-ATM) and 3p (FHIT) were chosen. Mutational testing for BRCA1 and BRCA2 was performed for cases where blood was available. Concordant LOH in both left and right tumours was demonstrated for at least one of the markers tested in 16/31(54%) cases. Where allelic loss was demonstrated for both left and right breast cancer, the same allele was lost on each occasion. This may suggest a common mutational event. Four cases showed concordant loss of alleles in both left and right breast cancer at D17S791 (BRCA1). BRCA1 mutations were identified in two of these cases where blood was available. Four cases showed concordant LOH at D13S155 (BRCA2). Concordant LOH was further demonstrated in seven cases for D11S1778 (ATM) and four cases for D3S1300 (which maps to the FHIT gene), suggesting a possible role for these tumour suppressor genes in this subgroup of breast cancer patients. No concordant allelic loss was demonstrated for D17S786 suggesting that germline mutations in p53 are unlikely in such cases of bilateral breast cancer.

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

Access this article

Log in via an institution

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. Knudson AG, Jr: Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68: 820-823, 1971

    Google Scholar 

  2. Smith SA, Easton DF, Evans DGR, Ponder BAJ: Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wild-type chromosome. Nature Genet 2: 128-131, 1992

    Google Scholar 

  3. Tsuda H, Hirohashi: Identification of multiple breast cancers of multicentric origin by histological; observations and distribution of allele loss on chromosome 16q. Cancer Res 55: 3395-3398, 1995

    Google Scholar 

  4. Schildkraut JM, Collins NK, Dent GA, Tucker JA, Barrett JC, Berchuck A, Boyd J: Loss of heterozygosity on chromosome 17q11-21 in cancers of women who have both breast and ovarian cancer. Am J Obstet Gynaecol 172: 908-913, 1995

    Google Scholar 

  5. Anderson DE: Genetic study of breast cancer: identification of a high risk group. Cancer 34: 1090-1097, 1974

    Google Scholar 

  6. Anderson DE, Badzioch MD: Bilaterality in familial breast cancer patients. Cancer 56: 2092-2098, 1985

    Google Scholar 

  7. Ottman R, Pike MC, King M-C, Casagrande JT, Henderson BE: Familial breast cancer in a population-based series. Am J Epidemiol 123: 15-21, 1986

    Google Scholar 

  8. 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 19: 403-410, 1991

    Google Scholar 

  9. Ellis IO, Galea MH, Broughton N, Locker A, Blamey RW, Elston CW: Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long term follow-up. Histopathology 20: 479-489, 1992

    Google Scholar 

  10. Chaudary MA, Millis RR, Hoskins EOL, Halder M, Bulbrook RD, Cuzick J, Hayward JL: Bilateral primary breast cancer: a prospective study of disease incidence. Br J Surg 71: 711-714, 1984

    Google Scholar 

  11. Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH: Germline p53 mutations in cancer families. Science 250: 1233-1238, 1990

    Google Scholar 

  12. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bodgen R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannon-Albright L, Goldgar D, Wiseman R, Kamb A, Skolnick MHA: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66-71, 1994

    Google Scholar 

  13. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G, Barfoot R, Hamoudi R, Patel S, Rice C, Biggs P, Hashim Y, Smith A Connor F, Arason A, Gudmundsson J, Ficenec D, Kelsell D, Ford D, Tonin P, Bishop DT, Spurr NK, Ponder BAJ, Eeles R, Peto J, Devilee P, Cornelisse C, Lynch H, Narod S, Lenoir G, Egilsson V, Barkardottir RB, Easton DF, Bentley DR, Futreal PA, Ashworth A, Stratton MR: Identification of the breast cancer susceptibility gene BRCA2. Nature 378: 789-792, 1995

    Google Scholar 

  14. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NGJ, Taylor AMR, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y: A single Ataxia Telengiectasia gene with a product similar to PI-3 kinase. Science 268: 1749-1752, 1995

    Google Scholar 

  15. Otah M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K: The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84: 587-597, 1996

    Google Scholar 

  16. Man S, Ellis IO, Sibbering DM, Blamey RW, Brook JD: High levels of allele loss at the FHIT and ATM genes in non-comedo ductal carcinoma in situ and grade I tubular invasive breast cancers. Cancer Res 56: 5484-5489, 1996

    Google Scholar 

  17. Gayther SA, Harrington P, Russel P, Kharkevich G, Garkavtseva RF, Ponder BA, UKCCCR Familial Ovarian Cancer Study Group: Rapid Detection of regionally clustered germline BRCA1 mutations by multiplex heteroduplex analysis. Am J Hum Genet 58: 451-456, 1996

    Google Scholar 

  18. Plummer SJ, Anton-Culver H, Webster L, Noble B, Liao S, Kennedy A, Belinson J, Casey G: Detection of BRCA1 mutations by the protein truncation test. Hum Mol Genet 4(10): 1989-1991, 1995

    Google Scholar 

  19. Serova OM, Mazoyer S, Puget N, Dubois V, Tonin P, Shugart YY, Goldgar D, Narod SA, Lynch HT, Lenoir GM: Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes? Am J Hum Genet 60(3): 486-495, 1997

    Google Scholar 

  20. Easton DF, Bishop DT, Ford D, Crockford GP, The Breast Cancer Linkage consortium: Genetic linkage analysis in familial breast and ovarian cancer: results in 214 families. Am J Hum Genet 52: 678-701, 1993

    Google Scholar 

  21. Wooster R, Neuhausen SL, Mangion J, Quirk J, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D, Fields P, Marshall G, Narod S, Lenoir G, Lynch H, Feunteun J, Devilee P, Cornelisse C, Menko FH, Daly PA, Ormiston W, McManus R, Pye C, Lewis CM, Cannon-Albright LA, Peto J, Ponder BAJ, Skolnick MH, Easton DF, Goldgar DE, Stratton MR: Localisation of a breast cancer susceptibility gene BRCA2, to chromosome 13q12-13. Science 265: 2088-2090, 1994

    Google Scholar 

  22. Futreal PA, Soderquist P, Marks JR, Iglehart JD, Cochran C, Barrett JC, Wiseman R: Detection of frequent allelic loss on proximal chromosome 17q in sporadic breast carcinoma using microsatellite length polymorphisms. Cancer Res 52: 2626-2627, 1992

    Google Scholar 

  23. Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, Bennett LM, Haugen-Strano A, Swensen J, Miki Y, Eddington K, McClure M, Frye C, Weaver-Feldhaus, Ding W, Gholami Z, Soderkvist P, Terry L, Jhanwar S, Berchuck A, Inglehart JD, Marks J, Ballinger DG, Barrett JC, Skolnick M, Kamb A, Wiseman R: BRCA1 mutations in primary breast and ovarian carcinomas. Science 266: 120-122, 1994

    Google Scholar 

  24. Langston AA, Malone KE, Thompson JD, Daling JR, Ostrander EA: BRCA1 mutations in a population-based sample of young women with breast cancer. N Engl J Med 334: 137-142, 1996

    Google Scholar 

  25. Krainer M, Silva-Arrieta S, Fitzgerald MG, Shimada A, Ishioka C, Kanamaru R, MacDonald DJ, Unsal H, Finketstein DM, Bowcock A, Isselbacher KJ, Haber DA: Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer. N Engl J Med 336: 1416-1421, 1997

    Google Scholar 

  26. Marcus JN, Watson P, Page DL, Narod SA, Lenoir GM, Tonin P, Linder-Stevenson L, Salerno G, Conway TA, Lynch HT: Hereditary breast cancer — Pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 77: 697-709, 1996

    Google Scholar 

  27. Jacquemier J, Eisenger F, Birnbaum D, Sobol H: Histoprognostic grade in BRCA1-asscociated breast cancer. Lancet 345: 1503, 1995

    Google Scholar 

  28. Bignon Y-J, Fonck Y, Chassagne M-C: Histoprognostic grade in tumours from families with hereditary predisposition to breast cancer. Lancet 346: 258, 1995

    Google Scholar 

  29. Cleton-Jansen A-M, Collins N, Lakhani SR, Weissenbach J, Devilee P, Cornelisee CJ, Stratton MR: Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13. Br J Cancer 72: 1241-1244, 1995

    Google Scholar 

  30. Ramus SJ, Freidman LS, Gayther SA, Ponder BAJ, Bobrow JG, Van der Looji M, Papp J, Olah E: A breast/ovarian cancer patient with germline mutations in both BRCA1 and BRCA2. Nature Genet 15: 14-15, 1997

    Google Scholar 

  31. Kelsell DP, Spurr NK, Barnes DM, Gusterson B, Bishop DT: Combined loss of BRCA1/BRCA2 in grade 3 breast carcinomas. Lancet 347: 1554-1555, 1996

    Google Scholar 

  32. Kote-Jarai Z, Eeles RA: BRCA1, BRCA2 and their possible function in DNA damage response. Br J Cancer 81(7): 1099-1102, 1999

    Google Scholar 

  33. Swift M, Morrell D, Cromartie E, Chamberlain AR, Skolnick MH, Bishop DT: The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 39: 573-583, 1986

    Google Scholar 

  34. Swift M, Morrell D, Massey RB, Chase CL: Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 325: 1831-1836, 1991

    Google Scholar 

  35. Hampton MM, Mannermaa A, Winquist R, Alavaikko M, Blanko G, Taskinen PJ, Kiviniemi K, Newsham I, Cavenee WK, Evans GA: Loss of heterozygosity in sporadic human breast carcinoma: A common region between 11q22 and 11q23.3. Cancer Res 54: 4586-4589, 1994

    Google Scholar 

  36. Carter SL, Negrini M, Baffa R, Gillum DR, Rosen berg AL, Schwarz GF, Croce CM: Loss of hetreozygosity at 11q22-q23 in breast cancer. Cancer Res 54: 6270-6274, 1994

    Google Scholar 

  37. Vorechovsky I, Rasio D, Luo L, Monaco C, Hammarstrom L, Webster DB, Zaloudik J, Barbanti-Brodano G, James J, Russo G, Croce CM, Negrini M: The ATM gene susceptibility to breast cancer: analysis of 38 breast tumours reveals no evidence for mutation. Cancer Res 56: 2726-2732, 1996

    Google Scholar 

  38. Wooster R, Ford D, Mangion J, Ponder BAJ, Peto J, Easton DF, Stratton M: Absence of linkage to the ataxia telangiectasia locus in familial breast cancer. Hum Genet 92: 91-94, 1993

    Google Scholar 

  39. Cortessis V, Ingles S, Millikan R, Diep A, Gatti RA, Richardson L, Thompson WD, Paganini-Hill A, Sparkes RS, Haile RW: Linkage analysis of DRD2, a marker linked to the ataxia telangiectasia gene, in 64 families with premenopausal bilateral breast cancer. Cancer Res 53: 5083-5086, 1993

    Google Scholar 

  40. Li FP and Fraumeni JF: Soft tissue sarcomas, breast cancer and other neoplasms: a familial syndrome? Ann Int Med 71: 747-752, 1969

    Google Scholar 

  41. Sidransky D, Tokino T, Helzlsouer K, Zehnbauer B, Rausch G, Shelton B, Prestigiacomo, Vogelstein B, Davidson N: Inhereited p53 mutations in breast cancer. Cancer Res 52: 2984-2986, 1992

    Google Scholar 

  42. Zelada-Helman M, Borresen-Dale A-L, Claro A, Chen J, Skoog L, Lindblom A: Screening for TP53 mutations in patients and tumours from 109 Swedish breast cancer families. Br J Cancer 75: 1201-1204, 1997

    Google Scholar 

  43. Sozzi G, Veronese ML, Negrini M, Baffa R, Cotticelli MG, Inoue H, Tornielli M, Pilotti S, De Gregorio, Pastorino U, Pierotti A, Ohta M, Huebner K, Croce CM: The FHIT gene at 3p14.2 is abnormal in lung cancer. Cell 85: 17-26, 1996

    Google Scholar 

  44. Kastury K, Baffa R, Druck T, Ohta M, Cotticelli MG, Inoue H, Negrini M, Rugge M, Huang D, Croce CM, Palazzo J, Huebner K: Potential gastrointestinal tumour suppressor locus at 3p14.2 FRA3B site identified by homozygous deletions in tumour cell lines. Cancer Res 56: 978-983, 1996

    Google Scholar 

  45. Hayashi S, Tanimoto K, Hajiro-Nakanishi K, Tsuchiya E, Kurosumi M, Higashi Y, Imai K, Suga K, Nakachi K: Abnormal FHIT transcripts in human breast carcinomas: a clinicopathological and epidemiological analysis of 61 Japanese cases. Cancer Res 57(10): 1981-1985, 1997

    Google Scholar 

Download references

Authors
  1. J. Kollias
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Man
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Marafie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. Carpenter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Pinder
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. I.O. Ellis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R.W. Blamey
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. Cross
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J.D. Brook
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kollias, J., Man, S., Marafie, M. et al. Loss of Heterozygosity in Bilateral Breast Cancer. Breast Cancer Res Treat 64, 241–251 (2000). https://doi.org/10.1023/A:1026575619155

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026575619155

Search

Navigation