Summary
We analysed the involvement of known and putative tumour suppressor- and oncogene loci in ductal carcinoma in situ (DCIS) by microsatellite analysis (LOH), Southern blotting and comparative genomic hybridization (CGH). A total of 78 pure DCIS cases, classified histologically as well, intermediately and poorly differentiated, were examined for LOH with 76 markers dispersed along all chromosome arms. LOH on chromosome 17 was more frequent in poorly differentiated DCIS (70%) compared to well-differentiated DCIS (17%), whereas loss on chromosome 16 was associated with well- and intermediately differentiated DCIS (66%). For a subset we have done Southern blot- and CGH analysis. C-erbB2/neu was amplified in 30% of poorly differentiated DCIS. No amplification was found of c-myc, mdm2, bek, flg and the epidermal growth factor (EGF)-receptor. By CGH, most frequent alterations in poorly differentiated DCIS were gains on 8q and 17q22–24 and deletion on 17p, whereas in well-differentiated DCIS amplification on chromosome 1q and deletion on 16q were found. In conclusion, our data indicates that inactivation of a yet unknown tumour suppressor gene on chromosome 16q is implicated in the development of most well and intermediately differentiated DCIS whereas amplification and inactivation of various genes on chromosome 17 are implicated in the development of poorly differentiated DCIS. Furthermore these data show that there is a genetic basis for the classification of DCIS in a well and poorly differentiated type and support the evidence of different genetic routes to develop a specific type of carcinoma in situ of the breast.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Adams, JM, Harris, AW, Pinkert, CA, Corcoran, LM, Alexander, WS, Cory, S, Palmiter, RD & Brinster, RL (1985). The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318: 533–538.
Adnane, J, Gaudray, P, Dionne, CA, Crumley, G, Jaye, M & Schlessinger, J (1991). BEK and FLG, two receptors to the members of the FGF family are amplified in subsets of human breast cancers. Oncogene 6: 659–663.
Aldaz, CM, Chen, T, Sahin, A, Cunningham, J & Bondy, M (1995). Comparative allelotype of in situ and invasive human breast cancer high frequency of microsatellite instability in lobular breast carcinomas. Cancer Res 55: 3976–3981.
Berns, EMJJ, Klijn, JGM, van Putten, WLJ, van Staveren, IL, Portengen, H & Foekens, JA (1992). C-myc amplification is a better prognostic factor than HER-2/neu amplification in primary breast cancer. Cancer Res 52: 1107–1113.
Berx, G, Cleton-Jansen, A-M, Nollet, F, de Leeuw, WJF, van de Vijver, MJ, Cornelisse, CJ & van Roy, F (1995). E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO 14: 6107–6115.
Berx, G, Cleton-Jansen, A-M, Strumane, K, de Leeuw, WJF, Nollet, F, Van Roy, F & Cornelisse, CJ (1996). E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 13: 1919–1925.
Bobrow, LG, Happerfield, LC, Gregory, WM, Springall, RD & Millis, RR (1994). The classification of ductal carcinoma in situ and its association with biological markers. Semin Diagn Pathol 11: 199–207.
Chitemerere, M, Andersen, TI, Holm, R, Karlsen, F, Borresen, AL & Nesland, JM (1996). TP53 alterations in atypical ductal hyperplasia and ductal carcinoma in situ of the breast. Breast Cancer Res Treat 41: 103–109.
Cleton-Jansen, A-M, Moerland, EW, Kuipers-Dijkshoorn, NJ, Callen, DF, Sutherland, GR, Hansen, B, Devilee, P & Cornelisse, CJ (1994). At least two different regions are involved in allelic imbalance on chromosome 16q in breast cancer. Genes Chromosomes Cancer 9: 101–107.
Coene, ED, Schelfhout, V, Winkler, RA, Schelfhout, AM, van Roy, N, Grooteclaes, M, Speleman, F & de Potter, CR (1997). Amplification units and translocation at chromosome 17q and c-erbB2 overexpression in the pathogenesis of breast cancer. Virchows Arch 430: 365–372.
Devilee, P & Cornelisse, CJ (1994). Somatic changes in human breast cancer. Biochimica Biophysica Acta 1198: 113–130.
Done, SJ, Arneson, NCR, Özçelik, H, Redston, M & Andrulis, IL (1998). p53 mutations in mammary ductal carcinoma in situ but not in epithelial hyperplasias. Cancer Res 58: 785–789.
Fujii, H, Szumel, R, Marsh, C, Zhou, W & Gabrielson, E (1996). Genetic progression, histological grade, and allelic loss in ductal carcinoma in situ of the breast. Cancer Res 56: 5260–5265.
Gupta, PK, Sahota, A, Boyadjiev, SA, Bye, S, Shao, C, O'Neill, JP, Hunter, TC, Albertini, RJ, Stambrook, PJ & Tischfield, JA (1997). High frequency in vivo loss of heterozygosity is primarily a consequence of mitotic recombination. Cancer Res 57: 1188–1193.
Holland, R, Peterse, JL, Millis, RR, Eusebi, V, Faverly, D, van de Vijver, MJ & Zafrani, B (1994). Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 11: 167–180.
Isola, J, de Vries, S, Chu, L, Ghazvini, S & Waldman, F (1994). Analysis of changes in DNA sequence copy number by comparative genomic hybridization in archival paraffin embedded tumour samples. Am J Pathol 145: 1301–1308.
James, LA, Mitchell, ELD, Menasce, L & Varley, JM (1997). Comparative genomic hybridization of ductal carcinoma in situ of the breast: identification of regions of DNA amplification and deletion in common with invasive breast carcinoma. Oncogene 14: 1059–1065.
Kallioniemi, A, Kallioniemi, OP & Sudar, D et al (1992). Comparative genomic hybridization for molecular cytogenetic analysis of solid tumours. Science 258: 818–821.
Kallioniemi, OP, Kallioniemi, A & Piper, J (1994). Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumours. Genes Chromosomes Cancer 10: 231–243.
Kanai, Y, Oda, T, Tsuda, H, Ochiai, A & Hirohashi, S (1994). Point mutation of the E-cadherin gene in invasive lobular carcinoma of the breast. Japanese Journal of Cancer Research 85: 1035–1039.
Kuukasjarvi, T, Tanner, M, Pennanen, S, Karhu, R, Kallioniemi, O-P & Isola, J (1997). Genetic changes in intraductal breast cancer detected by comparative genomic hybridization. Am J Pathol 150: 1465–1471.
Livingstone, LR, White, A, Sprouse, J, Livanos, E, Jacks, T & Tlsty, TD (1992). Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70: 923–935.
Mack, L, Kerkvliet, N, Doig, G & O'Malley, FP (1997). Relationship of a new histological categorization of ductal carcinoma in situ of the breast with size and the immunohistochemical expression of p53, c-erbB2, BCL2 and Ki-67. Hum Pathol 28: 974–979.
Marchetti, A, Buttitta, F, Girlando, S, Dalla Parma, P, Pellegrini, S, Fina, P, Doglioni, C, Belilacqua, G & Barbareshi, M (1995). MDM2 alterations and mdm2 protein overexpression in breast carcinomas. J Pathol 175: 31–38.
Miki, Y, Swensen, J, Shattuck-Eidens, D, Futreal, PA & Harshman, K et al (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66–71.
Munn, KE, Walker, RA, Menasce, L & Varley, JM (1996). Mutations of the TP53 gene and allelic imbalance at chromosome 17p13 in ductal carcinoma in situ. Br J Cancer 74: 1578–1585.
Munn, KE, Walker, RA, Menasce, L & Varley, JM (1996). Allelic imbalance in the region of the BRCA1 gene in ductal carcinoma in situ of the breast. Br J Cancer 73: 636–639.
Murphy, DS, Hoare, SF, Going, JJ, Malon, EE, George, WD, Kaye, SB, Brown, R, Black, DM & Keith, WN (1995). Characterization of extensive genetic alterations in ductal carcinoma in situ by fluorescence in situ hybridization and molecular analysis. J Nat Cancer Inst 87: 1694–1704.
Oliner, JD, Kinzler, KW, Melzer, PS, George, D & Vogelstein, B (1992). Amplification of a gene encoding a p53 associated protein in human sarcomas. Nature 358: 80–83.
Radford, DM, Fair, KL, Phillips, NJ, Ritter, JH, Steinbrueck, T, Holt, MS & Donis-Keller, H (1995). Allelotyping of ductal carcinoma in situ of the breast: Deletion of loci 8p, 13q, 16q, 17p and 17q. Cancer Res 55: 3399–3405.
Sambrook, J, Fritsch, EF & Maniatis, T (1989). Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press: New York
Scott, MA, Lagios, MD, Axelsson, K, Rogers, LW, Anderson, TJ & Page, DL (1997). Ductal carcinoma in situ of the breast: reproducibility of histological subtype analysis. Hum Pathol 28: 967–973.
Silverstein, MJ, Poller, DN, Waisman, JR, Colburn, WJ, Barth, A, Gierson, ED, Lewinsky, B, Gamagami, P & Slamon, DJ (199?). Prognostic classification of breast ductal carcinoma in situ. Lancet 345: 1154–1157.
Simpson, JF, Quan, DE, O'Malley, F, Odom-Maryon, T & Clarke, PE (1997). Amplification of CCND1 and expression of its protein product, cyclin D1, in ductal carcinoma in situ of the breast. Am J Pathol 151: 161–168.
Tavassolli, FA (1992). Pathology of the Breast, Appleton & Lange: Norwalk CT
Tsuda, H, Callen, DF, Fukutomi, T, Nakamura, Y & Hirohashi, S (1994). Allele loss on chromosome 16q24.2-ter occurs frequently in breast cancers irrespective of differences in phenotype and extent of the spread. Cancer Res 54: 513–517.
Ullrich, A, Coussens, L, Hayflick, JS, Dull, TJ, Gray, A, Tam, AW, Lee, J & Yarden, Y (1984). Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309: 418–425.
Varley, JM, Swallow, JE, Brammar, WJ, Whittaker, JL & Walker, RA (1987). Alterations to either c-erbB2(neu) or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis. Oncogene 1: 423–430.
Vogelstein, B, Fearon, ER, Hamilton, SR, Kern, SE, Preisinger, AC, Leppert, M, Nakamura, Y, White, R, Smits, AM & Bos, JL (1988). Genetic alterations during colorectal tumour development. N Engl J Med 319: 525–532.
Vos, CBJ, Cleton-Jansen, A-M, Berx, G, de Leeuw, WJF, ter Haar, NT, Peterse, JL, Cornelisse, CJ & van de Vijver, MJ (1997). E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumourigenesis. Br J Cancer 76: 1131–1133.
Yamamoto, T, Ikawa, S, Akiyama, T, Semba, K, Nomura, N, Miyajima, N, Saito, T & Toyoshima, K (1986). Similarity of protein encoded by the human c-erb-B2 gene to epidermal growth factor receptor. Nature 319: 230–234.
Zafrani, B, Leroyer, A, Fourquet, A, Laurent, M, Trophilme, D, Validire, P & Sastre-Garau, X (1994). Mammographically detected ductal in situ carcinoma of the breast analyzed with a new classification. A study of 127 cases: correlation with estrogen and progesterone receptors, p53 and c-erbB2 proteins and proliferative activity. Semin Diagn Pathol 11: 208–214.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Vos, C., Haar, N., Rosenberg, C. et al. Genetic alterations on chromosome 16 and 17 are important features of ductal carcinoma in situ of the breast and are associated with histologic type. Br J Cancer 81, 1410–1418 (1999). https://doi.org/10.1038/sj.bjc.6693372
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.bjc.6693372
Keywords
This article is cited by
-
Role of columnar cell lesions in breast carcinogenesis: analysis of chromosome 16 copy number changes by multiplex ligation-dependent probe amplification
Modern Pathology (2018)
-
Multicolor immunofluorescence reveals that p63- and/or K5-positive progenitor cells contribute to normal breast epithelium and usual ductal hyperplasia but not to low-grade intraepithelial neoplasia of the breast
Virchows Archiv (2017)
-
The distribution of ductal carcinoma in situ (DCIS) grade in 4232 women and its impact on overdiagnosis in breast cancer screening
Breast Cancer Research (2016)
-
Appraisal of the technologies and review of the genomic landscape of ductal carcinoma in situ of the breast
Breast Cancer Research (2015)
-
Selection and evolution in the genomic landscape of copy number alterations in ductal carcinoma in situ (DCIS) and its progression to invasive carcinoma of ductal/no special type: a meta-analysis
Breast Cancer Research and Treatment (2015)
