Skip to main content
SpringerLink
Log in

Frequent loss of heterozygosity at the deleted in colorectal carcinoma gene locus and its association with histologic phenotypes in breast carcinoma

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Loss of heterozygosity (LOH) at the deleted in colorectal carcinoma gene (DCC), a tumour suppressor gene that encodes a protein with high homology to the neural cell adhesion molecule, was investigated in 42 surgical specimens of primary breast carcinoma. LOH was analysed in breast carcinoma by amplifying the DNA, spanning a variable number of tandem repeats site and a restriction fragment length polymorphism site within DCC, using the polymerase chain reaction (PCR). Cell sorting was used to enrich carcinoma cells. The expression of the DCC gene was also investigated using a reverse transcription-PCR method followed by Southern blot hybridization. LOH at the DCC locus was detected in 15 (51.7%) of 29 informative cases and 10 of 13 cases having DCC-LOH showed distinct reduction or loss of DCC expression. The DCC-LOH was closely associated with certain histological phenotypes; DCC-LOH was more frequent in scirrhous carcinomas than in solid-tubular ones (P<0.05), and was also more frequent in carcinomas with infiltration into fat tissue over the mammary gland than in those without infiltration (P<0.05). DCC-LOH was detected in invasive lobular carcinomas (2/2), but in none of the noninvasive ductal carcinomas (0/2). These observations suggest that malignant histological phenotypes are associated with DCC-LOH.

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. Bergerheim U, Nordenskjöld M, Collins VP (1989) Deletion mapping in human renal cell carcinoma. Cancer Res 49:1390–1396

    Google Scholar 

  2. Bièche I, Champème M-H, Matifas F, Cropp CS, Callahan R, Lidereau R (1993) Two distinct regions involved in 1p deletion in human primary breast cancer. Cancer Res 53:1990–1994

    Google Scholar 

  3. Borg Å, Zhang Q-X, Alm P, Olsson H, Sellberg G (1992) The retinoblastoma gene in breast cancer: Allele loss is not correlated with loss of gene protein expression. Cancer Res 52:2991–2994

    Google Scholar 

  4. Chen L-C, Dollbaum C, Smith HS (1989) Loss of heterozygosity on chromosome lq in human breast cancer. Proc Natl Acad Sci USA 86:7204–7207

    Google Scholar 

  5. Chen L-C, Neubauer A, Kurisu W, Waldman FM, Ljung B-M, Goodson W III, Goldman ES, Moore D II, Balazs M, Liu E, Mayall BH, Smith HS (1991) 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 USA 88:3847–3851

    Google Scholar 

  6. Chenevix-Trench G, Leary J, Kerr J, Michel J, Kefford R, Hurst T, Parsons PG, Friedlander M, Khoo SK (1992) Frequent loss of heterozygosity on chromosome 18 in ovarian adenocarcinoma which does not always include the DCC locus. Oncogene 7:1059–1065

    Google Scholar 

  7. Cropp CS, Lidereau R, Campbell G, Champene MH, Callahan R (1990) Loss of heterozygosity on chromosomes 17 and 18 in breast carcinoma: Two additional regions identified. Proc Natl Acad Sci USA 87:7737–7741

    Google Scholar 

  8. Devilee P, Broek M van den, Kuipers-Dijkshoorn N, Kolluri R, Khan PM, Pearson PL, Cornelisse CJ (1989) At least four different chromosomal regions are involved in loss of heterozygosity in human breast carcinoma. Genomics 5:554–560

    Google Scholar 

  9. Devilee P, Vliet M van, Kuipers-Dijkshoorn N, Pearson PL, Cornelisse CJ (1991) Somatic genetic changes on chromosome 18 in breast carcinomas: is the DCC gene involved? Oncogene 6:311–315

    Google Scholar 

  10. Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW, Vogelstein B (1990) Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247:49–56

    Google Scholar 

  11. Gao X, Honn KV, Grignon D, Sakr W, Chen YQ (1993) Frequent loss of expression and loss of heterozygosity of the putative tumor suppressor gene DCC in prostatic carcinomas. Cancer Res 53:2723–2727

    Google Scholar 

  12. Greenwald BD, Harpaz N, Yin J, Huang Y, Tong Y, Brown VL, McDaniel T, Newkirk C, Resau JH, Meltzer SJ (1992) Loss of heterozygosity affecting the p53, Rb, and mcc/apc tumor suppressor gene loci in dysplastic and cancerous ulcerative colitis. Cancer Res 52:741–745

    Google Scholar 

  13. Hedrick L, Cho KR, Fearon ER, Wu T-C, Kinzler KW, Vogelstein B (1994) The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev 8:1174–1183

    Google Scholar 

  14. Höhne MW, Halatsch M-E, Kahl GF, Weinel RJ (1992) Frequent loss of expression of the potential tumor suppressor gene DCC in ductal pancreatic adenocarcinoma. Cancer Res 52:2616–2619

    Google Scholar 

  15. Kikuchi-Yanoshita R, Konishi M, Fukunari H, Tanaka K, Miyaki M (1992) Loss of expression of the DCC gene during progression of colorectal carcinomas in familial adenomatous polyposis and non-familial adenomatous polyposis patients. Cancer Res 52:3801–3803

    Google Scholar 

  16. Knudson AG (1971) Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823

    Google Scholar 

  17. Linnemann D, Raz A, Bock E (1989) Differential expression of cell adhesion molecules in variants of K1735 melanoma cells differing in metastatic capacity. Int J Cancer 43:709–712

    PubMed  Google Scholar 

  18. Mackay J, Steel CM, Elder PA, Forrest APM, Evans HJ (1988) Allele loss on short arm of chromosome 17 in breast cancers. Lancet 2:1384–1385

    Google Scholar 

  19. Merlo GR, Venesio T, Bernardi A, Canale L, Gaglia P, Lauro D, Cappa APM, Callahan R, Liscia DS (1992) Loss of heterozygosity on chromosome 17p13 in breast carcinomas identifies tumors with high proliferation index. Am J Pathol 140:215–223

    Google Scholar 

  20. Nakajima-Iijima S, Hamada H, Reddy P, Kakunaga T (1985) Molecular structure of the human cytoplasmic β-actin gene: Interspecies homology of sequences in the introns. Proc Natl Acad Sci USA 82:6133–6137

    Google Scholar 

  21. Narayanan R, Lawlor KG, Schaapveld RQJ, Cho KR, Vogelstein B, Tran PB-V, Osborne MP, Telang NT (1992) Antisense RNA to the putative tumor-suppressor gene DCC transforms Rat-1 fibroblasts. Oncogene 7:553–561

    Google Scholar 

  22. Ookawa K, Sakamoto M, Hiroshashi S, Yoshida Y, Sugimura T, Terada M, Yokota J (1993) Concordant p53 and DCC alterations and allelic losses on chromosomes 13q and 14q associated with liver metastases of colorectal carcinoma. Int J Cancer 53:382–387

    Google Scholar 

  23. Osborne RJ, Merlo GR, Mitsudomi T, Venesio T, Liscia DS, Cappa APM, Chiba I, Takahashi T, Nau MM, Callahan R, Minna JD (1991) Mutations in the p53 gene in primary human breast cancers. Cancer Res 51:6194–6198

    Google Scholar 

  24. Page DL, Anderson TJ (1987) Diagnostic histopathology of the breast. Churchill Livingstone, Edinburgh, pp 193–235

    Google Scholar 

  25. Sato T, Akiyama F, Sakamoto G, Kasumi F, Nakamura Y (1991) Accumulation of genetic alterations and progression of primary breast cancer. Cancer Res 51:5794–5799

    Google Scholar 

  26. Sato T, Tanigami A, Yamakawa K, Akiyama F, Kasumi F, Sakamoto G, Nakamura Y (1990) Allelotype of breast cancer: Cumulative allele losses promote tumor progression in primary breast cancer. Cancer Res 50:7184–7189

    Google Scholar 

  27. Takita K, Sato T, Miyagi M, Watatani M, Akiyama F, Sakamoto G, Kasumi F, Abe R, Nakamura Y (1992) 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 52:3914–3917

    Google Scholar 

  28. Tamura G, Kihana T, Nomura K, Terada M, Sugimura T, Hiroshashi S (1991) Detection of frequent p53 gene mutations in primary gastric cancer by cell sorting and polymerase chain reaction single-strand conformation polymorphism analysis. Cancer Res 51:3056–3058

    Google Scholar 

  29. Tamura G, Maesawa C, Suzuki Y, Kashiwaba M, Ishida M, Saito K, Satodate R (1994) Improved detection of loss of heterozygosity at retinoblastoma gene locus in human breast carcinoma. Pathol Int 44:34–38

    Google Scholar 

  30. Tanaka K, Oshimura M, Kikuchi R, Seki M, Hayashi T, Miyaki M (1991) Suppression of tumorigenicity in human colon carcinoma cells by introduction of normal chromosome 5 or 18. Nature 349:340–342

    Google Scholar 

  31. Thompson AM, Morris RG, Wallace M, Wyllie AH, Steel CM, Carter DC (1993) Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer. Br J Cancer 68:64–68

    Google Scholar 

  32. Uchino S, Tsuda H, Noguchi M, Yokota J, Terada M, Saito T, Kobayashi M, Sugimura T, Hirohashi S (1992) Frequent loss of heterozygosity at the DCC locus in gastric cancer. Cancer Res 52:3099–3102

    Google Scholar 

  33. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AMM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532

    CAS  PubMed  Google Scholar 

  34. Yamaguchi T, Toguchida J, Yamamuro T, Kotoura Y, Takada N, Kawaguchi N, Kaneko Y, Nakamura Y, Sasaki MS, Ishizaki K (1992) Allelotype analysis in osteosarcomas: Frequent allele loss on 3q, 13q, 17p, and 18q. Cancer Res 52:2419–2423

    Google Scholar 

  35. Yokota J, Wada M, Shimosato Y, Terada M, Sugimura T (1987) Loss of heterozygosity on chromosomes 3, 13 and 17 in small-cell carcinoma and on chromosome 3 in adenocarcinoma of the lung. Proc Natl Acad Sci USA 84:9252–9256

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Iwate Medical University School of Medicine, Uchimaru 19-1, 020, Morioka, Japan

    M. Kashiwaba & G. Tamura

  2. Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan

    M. Ishida

Authors
  1. M. Kashiwaba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Ishida
    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

Kashiwaba, M., Tamura, G. & Ishida, M. Frequent loss of heterozygosity at the deleted in colorectal carcinoma gene locus and its association with histologic phenotypes in breast carcinoma. Vichows Archiv A Pathol Anat 426, 441–446 (1995). https://doi.org/10.1007/BF00193166

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00193166

Key words

Search

Navigation