Abstract
The prognostic value of disseminated tumour cells derived from 353 breast cancer patients was evaluated. Disseminated tumour cells were purified from blood using a newly established method and nucleic acids were subsequently isolated. We investigated genomic imbalances (GI) such as mutation, amplification and loss of heterozygosity of 13 tumour suppressor genes and 2 proto-oncogenes using DNA from isolated minimal residual cancer cells. Significant correlations were found between genomic alterations of the DCC - and c-erbB-2 genes in disseminated breast cancer cells and actuarial relapse-free survival. Furthermore, increasing numbers of genomic imbalances measured in disseminated tumour cells were significantly associated with worse prognosis of recurrent disease. Logistic regression and Cox multivariate analysis led to the identification of genomic imbalances as an independent prognostic factor. Determination of disseminated tumour cells by genotyping of oncogenes and tumour suppressor genes seems not only to be a useful adjunct in follow up of carcinoma patients but provides also valuable additional individualized prognostic and predictive information in breast cancer patients beyond the TNM system. © 2000 Cancer Research Campaign http://www.bjcancer.com
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References
Aigner S, Sthoeger ZM, Fogel M, Weber E, Zarn J, Ruppert M, Zeller Y, Vestweber D, Stahel R, Sammar M and Altevogt P (1997) CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells. Blood 89: 3385–3395
Al-Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A and Muschel RJ (2000) Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med 6: 100–102
Aubele M, Mattis A, Zitzelsberger H, Walch A, Kremer M, Hutzler P, Hofler H and Werner M (1999) Intratumoral heterogeneity in breast carcinoma revealed by laser-microdissection and comparative genomic hybridization. Cancer Genet Cytogenet 110: 94–102
Brandt B, Roetger A, Heidl S, Jackisch C, Lelle RJ, Assmann G and Zanker KS (1998) Isolation of blood-borne epithelium-derived c-erbB-2 oncoprotein-positive clustered cells from the peripheral blood of breast cancer patients. Int J Cancer 76: 824–828
Carter SL, Negrini M, Baffa R, Gillum DR, Rosenberg AL, Schwartz GF and Croce CM (1994) Loss of heterozygosity at 11q22-q23 in breast cancer. Cancer Res 54: 6270–6274
Cawkwell L, Bell SM, Lewis FA, Dixon MF, Taylor GR and Quirke P (1993) Rapid detection of allele loss in colorectal tumours using microsatellites and fluorescent DNA technology. Br J Cancer 67: 1262–1267
Cawkwell L, Lewis FA and Quirke P (1994) Frequency of allele loss of DCC, p53, RBI, WT1, NF1, NM23 and APC/MCC in colorectal cancer assayed by fluorescent multiplex polymerase chain reaction. Br J Cancer 70: 813–818
Chen PH, Lin SY, Wang CK, Chen YJ, Chen TC and Chang JG (1993) “Hot spots” mutation analysis of p53 gene in gastrointestinal cancers by amplification of naturally occurring and artificially created restriction sites. Clin Chem 39: 2186–2191
Cho JH, Noguchi M, Ochiai A and Hirohashi S (1996) Loss of heterozygosity of multiple tumor suppressor genes in human gastric cancers by polymerase chain reaction. Lab Invest 74: 835–841
Crundwell MC, Chughtai S, Knowles M, Takle L, Luscombe M, Neoptolemos JP, Morton DG and Phillips SM (1996) Allelic loss on chromosomes 8p, 22q and 18q (DCC) in human prostate cancer. Int J Cancer 69: 295–300
de Graaf H, Maelandsmo GM, Ruud P, Forus A, Oyjord T, Fodstad O and Hovig E (1997) Ectopic expression of target genes may represent an inherent limitation of RT-PCR assays used for micrometastasis detection: studies on the epithelial glycoprotein gene EGP-2. Int J Cancer 72: 191–196
Denis MG, Lipart C, Leborgne J, LeHur PA, Galmiche JP, Denis M, Ruud E, Truchaud A and Lustenberger P (1997) Detection of disseminated tumor cells in peripheral blood of colorectal cancer patients. Int J Cancer 74: 540–544
Engel H, Kleespies C, Friedrich J, Breidenbach M, Kallenborn A, Schondorf T, Kolhagen H and Mallmann P (1999) Detection of circulating tumour cells in patients with breast or ovarian cancer by molecular cytogenetics. Br J Cancer 81: 1165–1173
Friedl P, Noble PB, Walton PA, Laird DW, Chauvin PJ, Tabah RJ, Black M and Zanker KS (1995) Migration of coordinated cell clusters in mesenchymal and epithelial cancer explants in vitro. Cancer Res 55: 4557–4560
Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millasseau P, Marc S, Bernardi G, Lathrop M and Weissenbach J (1994) The 1993–94 Genethon human genetic linkage map [see comments]. Nat Genet 7: 246–339
Hampl M, Hampl JA, Reiss G, Schackert G, Saeger HD and Schackert HK (1999) Loss of heterozygosity accumulation in primary breast carcinomas and additionally in corresponding distant metastases is associated with poor outcome. Clin Cancer Res 5: 1417–1425
Harada Y, Katagiri T, Ito I, Akiyama F, Sakamoto G, Kasumi F, Nakamura Y and Emi M (1994) Genetic studies of 457 breast cancers. Clinicopathologic parameters compared with genetic alterations [see comments]. Cancer 74: 2281–2286
Hardingham JE, Kotasek D, Farmer B, Butler RN, Mi JX, Sage RE and Dobrovic A (1993) Immunobead-PCR: a technique for the detection of circulating tumor cells using immunomagnetic beads and the polymerase chain reaction. Cancer Res 53: 3455–3458
Hauge XY, Evans GA and Litt M (1991) Dinucleotide repeat polymorphism at the D11S528 locus. Nucleic Acids Res 19: 1964
Heide I, Thiede C, Sonntag T, de Kant E, Neubauer A, Jonas S, Peter FJ, Neuhaus P, Hermann R, Huhn D and Rochlitz CF (1997) The status of p53 in the metastatic progression of colorectal cancer. Eur J Cancer 33: 1314–1322
Huang Y, Boynton RF, Blount PL, Silverstein RJ, Yin J, Tong Y, McDaniel TK, Newkirk C, Resau JH and Sridhara R (1992) Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers. Cancer Res 52: 6525–6530
Kirchweger R, Zeillinger R, Schneeberger C, Speiser P, Louason G and Theillet C (1994) Patterns of allele losses suggest the existence of five distinct regions of LOH on chromosome 17 in breast cancer. Int J Cancer 56: 193–199
Leitzel K, Lieu B, Curley E, Smith J, Chinchilli V, Rychlik W and Lipton A (1998) Detection of cancer cells in peripheral blood of breast cancer patients using reverse transcription-polymerase chain reaction for epidermal growth factor receptor. Clin Cancer Res 4: 3037–3043
Liggett WH, Jr and Sidransky D (1998) Role of the p16 tumor suppressor gene in cancer. J Clin Oncol 16: 1197–1206
Lizard Nacol S, Riedinger JM, Lizard G, Glasser AL, Coudray N, Chaplain G and Guerrin J (1997) Loss of heterozygosity at the TP53 gene: independent occurrence from genetic instability events in node-negative breast cancer. Int J Cancer 72: 599–603
Lopez Guerrero JA, Bolufer Gilabert P, Sanz Alonso M, Barragan Gonzalez E, Palau Perez J, De la Rubia Comos J, Sempere Talens A and Bonanad Boix S (1997) Minimal illegitimate levels of cytokeratin K19 expression in mononucleated blood cells detected by a reverse transcription PCR method (RT-PCR). Clin Chim Acta 263: 105–116
McGee TL, Yandell DW and Dryja TP (1989) Structure and partial genomic sequence of the human retinoblastoma susceptibility gene. Gene 80: 119–128
Naume B, Borgen E, Nesland JM, Beiske K, Gilen E, Renolen A, Ravnas G, Qvist H, Karesen R and Kvalheim G (1998) Increased sensitivity for detection of micrometastases in bone-marrow/peripheral-blood stem-cell products from breast-cancer patients by negative immunomagnetic separation. Int J Cancer 78: 556–560
Nawroz H, Koch W, Anker P, Stroun M and Sidransky D (1996) Microsatellite alterations in serum DNA of head and neck cancer patients. Nat Med 2: 1035–1037
Nemoto T, Vana J, Bedwani RN, Baker HW, McGregor FH and Murphy GP (1980) Management and survival of female breast cancer: results of a national survey by the American College of Surgeons. Cancer 45: 2917–2924
Offner S, Schmaus W, Witter K, Baretton GB, Schlimok G, Passlick B, Riethmuller G and Pantel K (1999) p53 gene mutations are not required for early dissemination of cancer cells. Proc Natl Acad Sci USA 96: 6942–6946
Soria JC, Gauthier LR, Raymond E, Granotier C, Morat L, Armand JP, Boussin FD and Sabatier L (1999) Molecular detection of telomerase-positive circulating epithelial cells in metastatic breast cancer patients. Clin Cancer Res 5: 971–975
van Leeuwen C, Tops C, Breukel C, van der Klift H, Fodde R and Khan PM (1991) CA repeat polymorphism at the D5S299 locus linked to adenomatous polyposis coli (APC). Nucleic Acids Res 19: 5805
Villuendas R, Sanchez-Beato M, Martinez JC, Saez AI, Martinez-Delgado B, Garcia JF, Mateo MS, Sanchez-Verde L, Benitez J, Martinez P and Piris MA (1998) Loss of p16/INK4A protein expression in non-Hodgkin's lymphomas is a frequent finding associated with tumor progression. Am J Pathol 153: 887–897
Zippelius A, Kufer P, Honold G, Kollermann MW, Oberneder R, Schlimok G, Riethmuller G and Pantel K (1997) Limitations of reverse-transcriptase polymerase chain reaction analyses for detection of micrometastatic epithelial cancer cells in bone marrow. J Clin Oncol 15: 2701–2708
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Austrup, F., Uciechowski, P., Eder, C. et al. Prognostic value of genomic alterations in minimal residual cancer cells purified from the blood of breast cancer patients. Br J Cancer 83, 1664–1673 (2000). https://doi.org/10.1054/bjoc.2000.1501
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DOI: https://doi.org/10.1054/bjoc.2000.1501
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