Abstract
Brain metastasis is the most common intracranial malignancy in adults, occurring in about 10 to 30% of adult cancer patients. Tumor metastasis is a complex process requiring cell motility, invasion, platelet aggregation ability, angiogenesis, and avoidance of host immune responses. Increasing gene dosage through oncogene copy gain (extra copies) or amplification is a common genetic mechanism for up-regulation of gene expression; this mechanism participates in the development of solid tumors and metastases by stimulation of cell division or by inhibition of cell death or cell cycle arrest. Using quantitative real time polymerase chain reaction we determined gene dosage of eight tumor-related genes: ELF3, MDM4, LRRN2, PDGFRA, EGFR, MYC, MDM2, and ERBB2, in a series of 18 brain metastases originated from lung cancer (six cases), breast carcinoma (three cases), melanoma (three samples), ovarian carcinoma (two cases), and one each from colon, bladder, kidney and undifferentiated carcinoma. Copy gains, in at least one gene, were identified in ten cases (55%) whereas amplification could be determined in six samples (33%). Concurrent alterations were observed in three lesions derived from two lung carcinoma and from one ovarian carcinoma: one of the lung carcinoma metastases accumulated copy gains of LRRN2, MDM2, PDGFRA, and ERBB2, whereas the second displayed amplification of LRNN2 and ERBB2. The lesion derived from the ovarian carcinoma accumulated amplification of MYC and EGFR. Differential amplification levels could be determined for the intracellular / extracellular domains of genes EGFR and/or ERBB2 in four cases. These data suggest that copy gain/gene amplification appears associated with greater tumor aggressiveness and that quantitative real time polymerase chain reaction is an alternative methodology to identify differential intragenic amplification levels.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Alonso, M.E., Bello, M.J., Arjona, D., Martinez-Glez, V., de Campos, J.M., Isla, A., Kusak, M.E., Vaquero, J., Gutierrez, M., Sarasa, J.L., and Rey, J.A. (2005) Real-time quantitative PCR analysis of gene dosages reveals amplification in low-grade oligodendrogliomas. Am. J. Clin. Pathol. 123:900–906
Arai, T., Ichimura, K., Hirakawa, K., and Yuasa, Y. (1994) DNA amplifications and elevated expression of proto-oncogenes in addition to altered DNA ploidy in metastatic brain tumors. Clin. Exp. Metastasis 12:267–275
Arjona, D., Bello, M.J., Alonso, M.E., Isla, A., de Campos, J.M., Vaquero, J., Sarasa, J.L., Gutierrez, M.,and Rey, J.A. (2005) Real-time quantitative PCR análisis of regions envolved in gene amplification reveals gene overdose in low-grade astrocytic gliomas. Diagn. Mol. Pathol. 14:224–229
Blanquicett, C., Johnson, M.R., Heslin, M., and Diasio, R.B. (2002) Housekeeping gene variability in normal and carcinomatous colorectal and liver tissues: application in pharmacogenomic gene expression studies. Anal. Biochem. 19:209–214
Brodeur, G.M., and Hogarty, M.D. (1998) Gene amplification in human cancers: biological and clinical significance. In: Vogelstein, B., Kinzler, K.W. (eds) The genetic basis of human cancer. McGraw-Hill, New York, pp. 161–172
Collins, V.P. (1995) Gene amplification in human gliomas. Glia 15:289–296
Franco-Hernandez, C., Martinez-Glez, V., Arjona, D.,de Campos, J.M., Isla, A., Gutierrez, M., Vaquero, J., and Rey, J.A. (2007) EGFR sequence variations and real.time quantitative polymerase Caín reaction análisis of gene dosage in brain metastases of solid tumors. Cancer Genet. Cytogenet. 173:63–67
Franco-Hernandez, C., Martinez-Glez, V., de Campos, J.M., Isla, A., Vaquero, J., and Rey, J.A. (2008) Detection of gene amplification and copy gains in brain metastases of solid tumors using quantitative real-tiem polymerase Caín reaction. Cancer Genet. Cytogenet. 182:61–62
Gonzalez-Gomez, P., Bello, M.J., Alonso, M.E., Lomas, J., Arjona, D., Amiñoso, C., de Campos, J.M., Isla, A., Gutierrez, M., and Rey, J.A. (2003) Frequent death-associated protein-kinase promoter hypermethylation in brain metastases of solid tumors. Oncol. Rep. 10:1031–1033
Gonzalez-Gomez, P., Bello, M.J., Alonso, M.E., Amiñoso, C., Lopez-Marin, I., de Campos, J.M., Isla, A., Gutierrez, M., and Rey, J.A. (2004) Promoter methylation of multiple genes in brain metastases of solid tumors. Int. J. Mol. Med. 13:93–98
Malden, M.T., Novak, U., Kaye, A.H., and Burgess, A.W. (1998) Selective amplification of the cytoplasmic domain of the epidermal growth factor receptor gene in glioblastoma multiforme. Cancer Res. 48:2711–2714
Martinez-Glez, V., Franco-Hernandez, C., Gonzalez-Gomez, P., Isla, A., de Campos, J.M., Vaquero, J., Gutierrez, M., Casartelli, C., and Rey, J.A. (2007) DAPK1 promoter hypermethylation in brain metastases and peripheral blood. Neoplasma 54:123–126
Nathoo, N., Chahlavi, A., Barnett, G.H., and Toms, S.A. (2005) Pathobiology of brain metastases. APMIS 100:713–719
Palmieri, D., Chambers, A.F., Felding-Habermann, B., Huang, S., and Steeg, P.S. (2007) The biology of metastasis to a sanctuary site. Clin. Cancer Res. 13:1656–1662
Petersen, I., Hidalgo, A., Petersen, S., Schlüns, K., Schewe, C., Pacyna-Gengelbach, M., Goeze, A., Krebber, B., Knösel, T., Kaufmann, O., Szymas, J., and von Deimling, A. (2000) Chromosomal imbalances in brain metastasis of solid tumors. Brain Pathol. 10:395–401
Wesseling, P., von Deimling, A., and Aldape, K.D. (2007) Metastatic tumours of the CNS. In: Luois, D.N., Ohgaki, H., Wiestler, O.D., Cavenee, W.K. (eds) WHO classification of tumours of the Central Nervous System. IARC, Lyon, pp. 247–252
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Netherlands
About this chapter
Cite this chapter
Franco-Hernandez, C. et al. (2011). Brain Metastases: Gene Amplification Using Quantitative Real-Time Polymerase Chain Reaction Analysis. In: Hayat, M. (eds) Methods of Cancer Diagnosis, Therapy, and Prognosis. Methods of Cancer Diagnosis, Therapy and Prognosis, vol 8. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-8665-5_6
Download citation
DOI: https://doi.org/10.1007/978-90-481-8665-5_6
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-90-481-8664-8
Online ISBN: 978-90-481-8665-5
eBook Packages: MedicineMedicine (R0)