Abstract
Metastases account for approximately 50% of the malignant tumors in the brain. In order to identify structural alterations that are associated with tumor dissemination into the central nervous system we used Comparative Genomic Hybridization (CGH) to investigate 42 brain metastases and 3 primary tumors of 40 patients. The metastases originated from lung cancer (14 cases), melanomas (7), carcinomas of breast (5), colon (5), kidney (5), adrenal gland (1) and thyroid (1). In addition, tumors of initially unknown primaries were assessed in 3 cases. The highest incidence of DNA gains were observed for the chromosomal regions 1q23, 8q24, 17q24‐q25, 20q13 (>80% of cases) followed by the gain on 7p12 (77%). DNA losses were slightly less frequent with 4q22, 4q26, 5q21, 9p21 being affected in at least 70% of the cases followed by deletions at 17p12, 4q32‐q34, 10q21, 10q23‐q24 and 18q21‐q22 in 67.5% of cases. Two unusual narrow regional peaks were observed for the gain on 17q24‐q25 and loss on 17p12.The incidence at individual loci can be viewed at our CGH online tumor database at http://www.amba.charite.de/cgh. The metastases of each tumor type showed a recurrent pattern of changes. In those cases with primary tumor and metastases available, the CGH pattern exhibited a high degree of conformity. In conclusion, our data suggests that specific genetic lesions are associated with tumor dissemination into the nervous system and that CGH analysis may be a useful supplementary tool for classification of metastases with unknown origin.
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References
- 1. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS (1997) AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277: 965–968. [DOI] [PubMed] [Google Scholar]
- 2. Brison O (1993) Gene amplification and tumor progression. Biochim Biophys Acta 1155: 25–41. [DOI] [PubMed] [Google Scholar]
- 3. Gronwald J, Storkel S, Holtgreve‐Grez H, Hadaczek P, Brinkschmidt C, Jauch A, Lubinski J, Cremer T (1997) Comparison of DNA gains and losses in primary renal clear cell carcinomas and metastatic sites: importance of 1q and 3p copy number changes in metastatic events. Cancer Res 57: 481–487. [PubMed] [Google Scholar]
- 4. Haataja L, Groffen J, Heisterkamp N (1997) Characterization of RAC3, a novel member of the Rho family. J Biol Chem 272: 20384–20388. [DOI] [PubMed] [Google Scholar]
- 5. Hamasaki H, Aoyagi M, Kasama T, Handa S, Hirakawa K, Taki T (1999) GT1b in human metastatic brain tumors: GT1b as a brain metastasis‐associated ganglioside. Biochim Biophys Acta 1437:93–99. [DOI] [PubMed] [Google Scholar]
- 6. Hartsough MT, Steeg PS (1998) Nm23‐H1: genetic alterations and expression patterns in tumor metastasis. Am J Hum Genet 63: 6–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Hidalgo A, Schewe C, Petersen S, Salcedo M, Gariglio P, Schlüns K, Dietel M, Petersen I (2000) Human Papilloma virus status and chromosomal imbalances in primary cervical carcinomas and tumor cell lines. European Journal of Cancer 36: 542–548. [DOI] [PubMed] [Google Scholar]
- 8. Kaufmann O, Dietel M (2000) Thyroid transcription factor 1 is the superior immunohistochemical marker for pulmonary adenocarcinomas and large cell carcinomas compared to Surfactant proteins A and B. Histopathology 36: 8–16. [DOI] [PubMed] [Google Scholar]
- 9. Knuutila S, Bjorkqvist AM, Autio K, Tarkkanen M, Wolf M, Mouni O, Szymanska J, Larramendy ML, Tapper J, Pere H, El‐Rifai W, Hemmer S, Wasenius VM, Vidgren V, Zhu Y (1998) DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies. Am J Pathol 152: 1107–1123. [PMC free article] [PubMed] [Google Scholar]
- 10. Kohno T, Kawanishi M, Matsuda S, Ichikawa H, Takada M, Ohki M, Yamamoto T, Yokota J (1998) Homozygous deletion and frequent allelic loss of the 21 q11. 1‐q21. 1 region including the ANA gene in human lung carcinoma. Genes Chromosomes Cancer 21:236–243. [DOI] [PubMed] [Google Scholar]
- 11. Kusuda J, Hidari N, Hirai M, Hashimoto K (1996) Sequence analysis of the cDNA for the human casein kinase 1‐delta (CSNK1D) gene and its chromosomal localization. Genomics 32: 140–143. [DOI] [PubMed] [Google Scholar]
- 12. Li C, Lusis AJ, Sparkes R, Nirula A, Gaynor R (1992) Characterization and chromosomal mapping of the gene encoding the cellular DNA binding protein ILF. Genomics 13: 665–671. [DOI] [PubMed] [Google Scholar]
- 13. Michiels F, Collard JG (1999) Rho‐like GTPases: their role in cell adhesion and invasion. Biochem Soc Symp 65: 125–146. [PubMed] [Google Scholar]
- 14. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R (1982) The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31: 11–24. [DOI] [PubMed] [Google Scholar]
- 15. Morse HG, Gonzalez R, Moore GE, Robinson WA (1992) Preferential chromosome 11 q and/or 17q aberrations in short‐term cultures of metastatic melanoma in resections from human brain. Cancer Genet Cytogenet 64: 118–126. [DOI] [PubMed] [Google Scholar]
- 16. Morse HG, Moore GE, Ortiz LM, Gonzalez R, Robinson WA (1994) Malignant melanoma: from subcutaneous nodule to brain metastasis. Cancer Genet Cytogenet 72: 16–23. [DOI] [PubMed] [Google Scholar]
- 17. Munier A, Feral C, Milon L, Pinon VPB, Gyapay G, Capeau J, Guellaen G, Lacombe ML (1998) A new human nm23 homologue (nm23‐H5) specifically expressed in testis germinal cells. FEBS Lett 434: 289–294. [DOI] [PubMed] [Google Scholar]
- 18. Nelson JS, von Deimling A, Janzer RC (1997) Metastatic tumours In: Pathology and genetics of tumours of the nervous system. Kleihues P, Cavenee WK (eds.) Chapter 16, pp. 200–202. International Agency for the Research on Cancer: Lyons , France . [Google Scholar]
- 19. Petersen I, Langreck H, Wolf G, Schwendel A, Psille R, Vogt P, Reichel MB, Ried T, Dietel M (1997) Small cell lung cancer is characterized by a high incidence of deletions on chromosomes 3p, 4q, 5q, 10q, 13q and 17p. Br J Cancer 75: 79–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Petersen I, Bujard M, Petersen S, Wolf G, Goeze A, Schwendel A, Langreck H, Gellert K, Reichel M, Just K, du Manoir S, Cremer T, Dietel M, Ried T (1997) Patterns of chromosomal imbalances in adenocarcinoma and squamous cell carcinoma of the lung. Cancer Res 57: 2331–2335. [PubMed] [Google Scholar]
- 21. Petersen S, Aninat‐Meyer M, Schlüns K, Gellert K, Dietel M, Petersen I (2000) Chromosomal alterations in the clonal evolution to the metastatic stage of squamous cell carcinomas of the lung. Br J Cancer 82: 65–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Reichel MB, Ohgaki H, Petersen I, Kleihues P (1994) p53 mutations in primary human lung tumors and their metastases. Mol Carcinogen 9: 105–109. [DOI] [PubMed] [Google Scholar]
- 23. Roth K, Wolf G, Dietel M and Petersen I (1997) Image analysis for Comparative Genomic Hybridization based on a karyotyping program for Windows. Anal Quant Cytol Histol 19: 461–474. [PubMed] [Google Scholar]
- 24. Ruan S, Fuller G, Levin V, Bruner JM, Zhang W (1998) Detection of p21WAF1/Cip1 in brain metastases. J Neurooncol 37: 223–228. [DOI] [PubMed] [Google Scholar]
- 25. Schwendel A, Langreck H, Reichel M, Schrück E, Ried T, Dietel M, Petersen I (1997) Primary small cell lung carcinomas and their metastases are characterized by a recurrent pattern of genetic alterations. Int J Cancer (Pred Oncol) 74: 86–93. [DOI] [PubMed] [Google Scholar]
- 26. Torp SH, Helseth E, Ryan L, Stolan S, Dalen A, Unsgaard G (1992) Expression of the epidermal growth factor receptor gene in human brain metastases. APMIS 100: 713–719. [DOI] [PubMed] [Google Scholar]
- 27. Wick W, Petersen I, Schnitzler R, Wolfarth B, Lenartz D, Bierhoff E, Hümmerich J, Stangl AP, Schramm J, Wiestler OD, von Deimling A (1996) Evidence for a novel tumor suppressor gene on chromosome 15 associated with progression to metastatic stage in breast cancer. Oncogene 12: 973–978. [PubMed] [Google Scholar]