Summary
The aim of the present study was to find out whether increasing malignancy of prostate carcinoma correlates with an overall increase of loss of heterozygosity (LOH), and whether LOH typing of microdissected tumour areas can help to distinguish between multifocal or clonal tumour development. In 47 carcinomas analysed at 25 chromosomal loci, the overall LOH rate was found to be significantly lower in grade 1 areas (2.2%) compared with grade 2 (9.4%) and grade 3 areas (8.3%, P = 0.007). A similar tendency was found for the mean fractional allele loss (FAL, 0.043 for grade 1, 0.2 for grade 2 and 0.23 for grade 3, P = 0.0004). Of 20 tumours (65%) with LOH in several microdissected areas, 13 had identical losses at 1–4 loci within two or three areas, suggesting clonal development of these areas. Markers near RB, DCC, BBC1, TP53 and at D13S325 (13q21–22) showed higher loss rates in grades 2 and 3 (between 25% and 44.4%) compared with grade 1 (0–6.6%). Tumour-suppressor genes (TSGs) near these loci might, thus, be important for tumour progression. TP53 mutations were detected in 27%, but BBC1 mutations in only 7%, of samples with LOH. Evaluation of all 25 loci in every tumour made evident that each prostate cancer has its own pattern of allelic losses.
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References
Adams, S. M., Helps, N. R., Sharp, M. G. F., Brammar, W. J., Walker, R. A. & Varley, J. M. (1992). Isolation and characterization of a novel gene with differential expression in benign and malignant human breast tumors. Hum Mol Genet 1: 91–96.
Bender, B., Wiestler, O. D. & von Deimling, A. (1994). A device for processing large acrylamide gels. Biotechniques 16: 204–206.
Böcking, A. & Sommerkamp, H. (1980). Histologisches Malignitätsgrading des Prostatakarzinoms. Ver Dtsch Ges Urol 32: 63–65.
Böcking, A., Kiehn, J. & Heinzel-Wach, M. (1982). Combined histologic grading of prostatic carcinoma. Cancer 50: 288–294.
Bookstein, R. (1994). Tumor suppressor genes in prostatic oncogenesis. J Cell Biochem, (suppl.) 19: 217–223.
Bookstein, R., Shew, J., Chen, P., Scully, P. & Lee, W. H. (1990). Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated Rb gene. Science 247: 712–715.
Bookstein, R., MacGrogan, D., Hilsenbeck, S. G., Sharkey, F. & Allred, D. C. (1993). p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res 53: 3369–3373.
Buttyan, R., Sawczuk, I. S., Benson, M. C., Siegal, J. D. & Olsson, C. A. (1987). Enhanced expression of the c-myc protooncogene in high-grade human prostate cancers. Prostate 11: 327–337.
Chi, S. G., de Vere-White, R. W., Meyers, F. J., Siders, D. B., Lee, F. & Gumerlock, P. H. (1994). p53 in prostate cancer: frequent expressed transition mutations. J Natl Cancer Inst 86: 926–933.
Cleton-Jansen, A. M., Moerland, H. W., Callen, D. F., Dogget, N. A., Devilee, P. & Cornelisse, C. J. (1995). Mapping of the breast basic conserved gene (D16S444E) to human chromosome band 16q24.3. Cytogenet Cell Genet 68: 49–51.
Cunningham, J. M., Shan, A., Wick, M. J., McDonnell, S. K., Schaid, D. J., Tester, D. J., Qian, J., Takahashi, S., Jenkins, R. B., Bostwick, D. G. & Thibodeau, S. N. (1996). Allelic imbalance and microsatellite instability in prostatic adenocarcinoma. Cancer Res 56: 4475–4482.
Dhom, G. (1991). Pathologie des männlichen Genitale, Tumoren der Prostata. Spezielle Pathologische Anatomie Band 21: 525–642.
Fleming, W. H., Hamel, A., MacDonald, R., Ramsey, E., Pettigrew, N. M., Johnston, B., Dodd, J. G. & Matusik, R. J. (1986). Expression of the c-myc protooncogene in human prostatic carcinoma and benign prostatic hyperplasia. Cancer Res 46: 1535–1538.
Gao, X., Honn, K. V., Grignon, D., Sakr, W. & Chen, Y-Q (1993). Frequent loss of expression and loss of heterozygosity of the putative tumor suppressor gene DCC in prostate carcinomas. Cancer Res 53: 2723–2727.
Gao, X., Porter, A. T. & Honn, K. V. (1995). Tumor suppressor genes and their involvement in human prostate cancer: Review. CMB 2: 475–498.
Gao, X., Zacharek, A., Grignon, D., Liu, H., Skr, W., Porter, A. T., Chen, Y. Q. & Honn, K. V. (1995). High frequency of loss of expression and allelic deletion of the APC and MCC genes in human prostate cancer. Int J Oncol 6: 111–117.
Gao, X., Zacharek, A., Salkowski, A., Grignon, D. J., Sakr, W., Porter, A. T. & Honn, K. V. (1995c). Loss of heterozygosity of the BRCA1 and other loci on chromosome 17q in human prostate cancer. Cancer Res 55: 1002–1005.
Gumerlock, P. H., Poonamallee, U. R., Mayers, F. J. & deVere White, R. W. (1991). Activated ras alleles in human carcinoma of the prostate are rare. Cancer Res 51: 1632–1637.
Hanash, K. A., Utz, D. C., Look, E. N. & Taylor, W. F. (1972). Cancer of the prostate: a 15 year follow-up. J Urol 107: 450–453.
Helpap, B., Böcking, A., Dhom, G., Faul, P., Kastendieck, H., Leistenschneider, W. & Müller, H. A. (1985). Klassifikation, histologisches und cytologisches Grading sowie Regressionsgrading des Prostatakarzinoms. Pathologe 6: 3–7.
Helps, N. R., Adams, S. M., Brammar, W. J. & Varley, J. M. (1995). The Drosophila melanogaster homologue of the human BBC1 gene is highly expressed during embryogenesis. Gene 162: 245–248.
Isaacs, W. B. (1995). Molecular genetics of prostate cancer. Cancer Surveys 25: 357–379.
Isaacs, W. B. & Carter, B. S. (1991). Genetic changes associated with prostate cancer in humans. Cancer Surveys 11: 15–53.
Konishi, N., Hiasa, Y., Matsuda, H., Tao, M., Tsuzuki, T., Hayashi, I., Kitahori, Y., Shiraishi, T., Yatani, R. & Shimazaki, J. (1995). Intratumor cellular heterogeneity and alterations in ras oncogene and p53 tumor suppressor gene in human prostate carcinoma. Am J Pathol 147: 1112–1122.
Kuhn, E. J., Kurnot, A., Sesterhenn, A., Chan, E. H. & Moul, J. W. (1993). Expression of the c-erbB-2 (HER-2/neu) oncoprotein in human prostatic carcinoma. J Urol 150: 1427–1433.
Latil, A., Fournier, G., Cussenot, O. & Lidereau, R. (1996). Differential chromosome allelic imbalance in the progression of human prostate cancer. J Urol 156: 2079–2083.
Lin, J., Wu, X., Chen, J., Chang, A. & Levine, A. J. (1994). Functions of the p53 protein in growth regulation and tumor suppression. Cold Spring Harbor Symp Quant Biol 59: 215–223.
Macdonald, F. & Ford, C. H. J. (1997). Molecular Biology of Cancer, BIOS Scientific Publishers: Oxford
Macoska, J. A., Trybus, T. M., Benson, P. D., Sakr, W. A., Grignon, D. J., Wojno, K. D., Pietruk, T. & Powell, I. J. (1995). Evidence for three tumor suppressor gene loci on chromosome 8p in human prostate cancer. Cancer Res 55: 5390–5395.
Mirchandani, D., Zheng, J., Miller, G. J., Ghosh, A. K., Shibata, D. K., Cote, R. J. & Roy-Burman, P. (1995). Heterogeneity in intratumor distribution of p53 mutations in human prostate cancer. Am J Pathol 147: 92–101.
Moul, J. W., Friedrichs, P. A., Lance, R. S., Theune, S. M. & Chang, E. (1992). Infrequent RAS oncogene mutations in human prostate cancer. Prostate 20: 327–338.
Navone, N. M., Troncoso, P., Pisters, L. L., Goodrow, T. L., Palmer, J. L., Nichols, W. W., von Eschenbach, A. C. & Conti, C. J. (1993). p53 protein accumulation and gene mutation in the progression of human prostate carcinoma. J Natl Cancer Inst 85: 1657–1669.
Peehl, D. M. (1993). Oncogenes in prostate cancer: an up-date. Cancer, (suppl.) 71: 1159–1164.
Sadasivan, R., Morgan, R., Jennings, S., Austenfeld, M., van Veldhuizen, P., Stephens, R. & Noble, M. (1993). Overexpression of HER-2/NEU may be an indicator of poor prognosis in prostate cancer. J Urol 150: 126–131.
Sandberg, A. A. (1992). Cytogenetic and molecular genetic aspects of human prostate cancer: primary and metastatic. In Karr JP and Yamanoka H (eds) Prostate Cancer and Bone Metastasis 324: 45–75.
Trapman, J., Sleddens, HFBM, van der Weiden, M. M., Dinjens, W. N. M., Konig, J. J., Schroder, F. H., Faber, P. W. & Bosman, F. T. (1994). Loss of heterozygosity of chromosome 8 microsatellite loci implicates a candidate tumor suppressor gene between the loci D8S87 and D8S133 in human prostate cancer. Cancer Res 54: 6061–6064.
Umbas, R., Schalken, J. A., Aalders, T. W., Carter, B. S., Karthaus, H. F. M., Schaafsma, H. E., Debruyne, F. M. J. & Isaacs, W. B. (1992). Expression of the cellular adhesions molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res 52: 5104–5109.
Viola, M. V., Fromowitz, F., Oravez, S., Deb, S., Finkel, G., Lundy, J., Hand, P., Thor, A. & Schlom, J. (1986). Expression of ras oncogene p21 in prostate cancer. N Engl J Med 314: 133–137.
Vocke, C. D., Pozzatti, R. O., Bostwick, D. G., Florence, C. D., Jennings, S. B., Strup, S. E., Duray, P. H., Liotta, L. A., Emmert-Buck, R. & Linehan, W. M. (1996). Analysis of 99 microdissected prostate carcinomas reveals a high frequency of allelic loss on chromosome 8p12–21. Cancer Res 56: 2411–2416.
von Deimling, A., Bender, B., Louis, D. N. & Wiestler, O. D. (1993). A rapid and non-radioactive PCR based assay for the detection of allelic loss in human gliomas. Neuropathol Appl Neurobiol 19: 524–529.
Wales, M. M., Biel, M. A., el Deiry, W., Nelkin, B. D., Issa, J. P., Cavenee, W. K., Kuerbitz, S. J. & Baylin, S. B. (1995). p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nature Med 1: 570–577.
Zenklusen, J. C., Thompson, J. C., Troncoso, P., Kagan, J. & Cont, C. J. (1994). Loss of heterozygosity in human primary prostate carcinomas: a possible tumor suppressor gene at 7q31.1. Cancer Res 54: 6370–6373.
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Hügel, A., Wernert, N. Loss of heterozygosity (LOH), malignancy grade and clonality in microdissected prostate cancer. Br J Cancer 79, 551–557 (1999). https://doi.org/10.1038/sj.bjc.6690087
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DOI: https://doi.org/10.1038/sj.bjc.6690087
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