Detección de aneuploidías del cromosoma 17 y deleción del gen TP53 en una amplia variedad de tumores sólidos mediante hibridación in situ fluorescente bicolor
Palabras clave:
aneuploidía, deleción cromosómica, gen Tp53, hibridación fluorescente in situ, neoplasias, inestabilidad cromosómica, heterogeneidad genética
Resumen
Introducción. El TP53 es un gen supresor de tumores localizado en la región cromosómica 17p13.1; controla el ciclo celular y se encuentra alterado en cerca de 50% de todas las neoplasias.Objetivos. Determinar las aneuploidías del cromosoma 17 y la deleción en el locus 17p13.1 del gen TP53, en diversos tumores sólidos primarios utilizando la técnica FISH-bicolor.
Materiales y métodos. Se analizaron 38 muestras de diversos tipos de tumores sólidos primarios. Todas las muestras se disociaron mecánica y enzimáticamente con colagenasa al 0,2%, antes de la obtención de los núcleos interfásicos. La técnica de FISH-bicolor se realizó en núcleos interfásicos, mediante sondas marcadas directamente con fluorocromos para el centrómero del cromosoma 17 (CEP 17; señal verde; VYSIS) y para el locus específico del gen TP53 (LSI 17p13.1; señal naranja; VYSIS).
Resultados. Se encontró que 63% (24/38) de las muestras tenían aneuploidías del cromosoma 17. La monosomía fue la aneuploidía más frecuente (75%; 18/24), seguida de la trisomía (17%; 4/24); la nulisomía y la tetrasomía fueron menos frecuentes. El 89,5% (34/38) de los casos presentaron deleción del gen TP53. Sólo cuatro casos fueron normales para el número de copias del cromosoma 17 y del gen TP53. El estudio histopatológico mostró que la mayoría de las muestras eran tumores malignos.
Conclusiones. La aneuploidía del cromosoma 17 y la deleción en el locus 17p13.1 del gen TP53 son alteraciones muy frecuentes en los tumores sólidos. La técnica FISH-bicolor permite detectar simultáneamente alteraciones cromosómicas numéricas y estructurales en núcleos interfásicos.
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Referencias bibliográficas
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17. Watters AD, Going JJ, Cooke TG, Bartlett JM. Chromosome 17 aneusomy is associated with poor prognostic factors in invasive breast carcinoma. Breast Cancer Res Treat. 2003;77:109-14.
18. Frau DV, Lai ML, Caria P, Dettori T, Coni P, Faa G, et al. Trisomy 17 as a marker for a subset of noninvasive thyroid nodules with focal features of papillary carcinoma: cytogenetic and molecular analysis of 62 cases and correlation with histological findings. J Clin Endocrinol Metab. 2008;93:177-81.
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22. Hardisson D, Álvarez-Marcos C, Salas-Bustamante A, Alonso-Guervós M, Sastre N, Sampedro A. Numerical aberrations of chromosomes 8, 9, 11, and 17 in squamous cell carcinoma of the pharynx and larynx: a fluorescence in situ hybridization and DNA flow cytometric analysis of 50 cases. Oral Oncol. 2004;40:409-17.
23. Gallucci M, Guadagni F, Marzano R, Leonardo C, Merola R, Sentinelli S, et al. Status of the p53, p16, RB1 and HER-2 genes and chromosomes 3, 7, 9, and 17 in advanced bladder cancer: correlation with adjacent mucosa and pathological parameters. J Clin Pathol. 2005;58:367-71.
24. Gotte K, Schafer C, Riedel F, Arens N, Hormann K. Intratumoral genomic heterogeneity in primary head and neck cancer and corresponding metastases detected by dual-FISH. Oncol Rep. 2004;11:17-23.
25. Risio M, Casorzoa L, Chiecchioa L, De Rosaa G, Rossinib F. Deletions of 17p are associated with transition from early to advanced colorectal cancer. Cancer Genet Cytogenet. 2003;147:44-9.
26. Gomyo Y, Osaki M, Kaibara N, Ito H. Numerical aberrations and point mutation of p53 gene in human gastric intestinal metaplasia and well-differenciated adenocarcinoma: analysis by fluorescence in situ hybridization (FISH) and PCR-SSCP. Int J Cancer. 1996;66:594-9.
27. Boveri T. Zur Frage der Entstehung maligner Tumoren. Jena: Gustar Fischer, Jena; 1914. p. 1-64.
28. Duesberg P, Li R, Rasnick D, Rausch C, Willer A, Kraemer A, et al. Aneuploidy precedes and segregates with chemical carcinogenesis. Cancer Genet Cytogenet. 2000;119:83-93.
29. Li L, McCormack AA, Nicholson JM, Fabarius A, Hehlmann R, Sachs RK, et al. Cancer-causing karyotypes: chromosomal equilibria between stabilizing aneuploidy and stabilizing selection for oncogenic function. Cancer Genet Cytogenet. 2009;188:1-25.
30. Kops GJ, Weaver BA, Cleveland DW. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer. 2005;5:773-85.
31. Michor F. Chromosomal instability and human cancer. Philos Trans R Soc Lond B Biol Sci. 2005;360:631-5.
32. Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature. 1997;386:623-7.
33. Liang Z, Zeng X, Gao J, Wu S, Wang P, Shi X, et al. Analysis of EGFR, HER, and TOP2A gene status and chromosomal polysomy in gastric adenocarcinoma from Chinese patients. BMC Cancer. 2008;8:363-72.
34. Reinholz MM, Bruzek AK, Visscher DW, Lingle WL, Schroeder MJ, Pérez EA, et al. Breast cancer and aneusomy 17: implications for carcinogenesis and therapeutic response. Lancet Oncol. 2009;10:267-77.
35. Takahasi Y, Nagata T, Asai S, Shintaku K, Eguchi T, Ishi Y, et al. Detection aberrations on 17p and gene in gastrointestinal cancers by dual (two-color) fluorescence in situ hybridization and GeneChip p53 assay. Cancer Genet Cytogenet. 2000;121:38-43.
36. Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J. Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol. 2009;27:1627-36.
37. Cesar AC, Borim AA, Caetano A, Cury PM, Silva AE. Aneuploidies, deletion, and overexpression of TP53 gene in intestinal metaplasia of patients without gastric cancer. Cancer Genet Cytogenet. 2004;153:127-32.
38. Veiga L, Bérgamo N, Kowalski L, Rogatto S. Classical and molecular cytogenetic analysis in head and neck squamous cell carcinomas. Genet Mol Biol. 2003;26:121-8.
39. Nahi H, Lehmann S, Bengtzen S, Jansson M, Möllgård L, Paul C, et al. Chromosomal aberrations in 17p predict in vitro drug resistance and short overall survival in acute myeloid leukemia. Leuk Lymphoma. 2008;49:508-16.
40. Fahmy M, Skacel M, Gramlich TL, Brainard JA, Rice TW, Goldblum JR, et al. Chromosomal gains and genomic loss of p53 and p16 genes in Barrett's esophagus detected by fluorescence in situ hybridization of cytology specimens. Mod Pathol. 2004;17:588-96.
41. Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer. 2001;1:157-62.42. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396:643-9.
43. Soussi T, Lozano G. p53 mutation heterogeneity in cancer. Biochem Biophys Res Commun. 2005;331:834-42.
44. Nowak MA, Michor F, Iwasa Y. Genetic instability and clonal expansion. J Theor Biol. 2006;241:26-32.
45. Yoshimura A, Sugihara H, Ling ZQ, Peng DF, Mukaisho K, Fujiyama Y, et al. How wild-type TP53 is inactivated in undifferentiated-type gastric carcinomas: analyses of intratumoral heterogeneity in deletion and mutation of TP53. Pathobiology. 2006;73:40-9.
46. Aguilera A, Gómez-González B. Genome instability: a mechanistic view of its causes and consequences. Nat Rev Genet. 2008;9:204-17.
47. Panani AD. Cytogenetic and molecular aspects of gastric cancer: clinical implications. Cancer Lett. 2008;266:99-115.
48. Montenegro Y, Ramírez-Castro JL , Isaza LF, Bedoya G, Muñetón-Peña CM. Análisis genético en pacientes con cáncer colorrectal. Rev Med Chil. 2006;134:1221-9.
49. Worthley DL, Whitehall VL, Spring KJ, Leggett BA. Colorectal carcinogenesis: road maps to cancer. World J Gastroenterol. 2007;13:3784-91.
2. Albertson DG, Collins C, McCormick F, Gray JW. Chromosome aberrations in solid tumors. Nat Genet. 2003;34:369-76.
3. Weaver BA, Cleveland DW. Does aneuploidy cause cancer? Curr Opin Cell Biol. 2006;18:658-67.
4. Fröhling S, Döhner H. Chromosomal abnormalities in cancer. N Engl J Med. 2008;359:722-34.
5. Duesberg P, Li R, Fabarius A, Hehlmann R. Aneuploidy and cancer: from correlation to causation. Contrib Microbiol. 2006;13:16-44.
6. Duesberg P, Rausch C, Rasnick D, Hehlmann R. Genetic instability of cancer cells is proportional to their degree of aneuploidy. Proc Natl Acad Sci USA. 1998;95:13692-7.
7. Strano S, Dell'Orso S, Di Agostino S, Fontemaggi G, Sacchi A, Blandino G. Mutant p53: an oncogenic transcription factor. Oncogene. 2007;26:2212-9.
8. Herrera JC, Vásquez G, Ramírez JL, Muñetón CM. Papel del gen TP53 en la oncogénesis. Salud UIS. 2004;26:88-99.
9. Petitjean A, Marcel V, Pétré A, Mounawar M, Plymoth A, de Fromentel CC, et al. Recent advances in p53 research: an interdisciplinary perspective. Cancer Gene Ther. 2009; 16:1-12.
10. Petitjean A, Achatz MI, Borresen-Dale AL, Hainaut P, Olivier M. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene. 2007;26:2157-65.
11. Ramírez GC, Herrera JC, Muñetón CM, Márquez JR, Isaza LF. Análisis de las aneuploidías del cromosoma 17 y deleción del gen TP53 en tumores gastrointestinales por FISH-bicolor. Rev Col Gastroenterol. 2008;23:333-42.
12. Herrera JC, Ramírez GC, Muñetón CM. Estudio de las aneuploidías del cromosoma 17 y la deleción del gen TP53 en neoplasias hematológicas, por la técnica del FISH-bicolor. Iatreia. 2008;21:364-74.
13. Levsky JM, Singer RH. Fluorescence in situ hybridization: past, present and future. J Cell ScI. 2003;116:2833-8.
14. James L, Varley J. Advances in cytogenetic analysis of solid tumours. Cromosome Res. 1996:4:479-85.
15. Rao PH, Mathew S, Lauwers G, Rodríguez E, Kelsen DP, Chaganti RS. Interphase cytogenetics of gastric and esophageal adenocarcinomas. Diagn Mol Pathol. 1993;2:264-8.
16. Kawai T, Hiroi S, Nakanishi K, Sakurai Y, Torikata C. Abnormalities in chromosome 17and p53 in lung carcinoma cells detected by fluorescence in situ hybridization. Pathol Int. 2004;54:413-9.
17. Watters AD, Going JJ, Cooke TG, Bartlett JM. Chromosome 17 aneusomy is associated with poor prognostic factors in invasive breast carcinoma. Breast Cancer Res Treat. 2003;77:109-14.
18. Frau DV, Lai ML, Caria P, Dettori T, Coni P, Faa G, et al. Trisomy 17 as a marker for a subset of noninvasive thyroid nodules with focal features of papillary carcinoma: cytogenetic and molecular analysis of 62 cases and correlation with histological findings. J Clin Endocrinol Metab. 2008;93:177-81.
19. Bergamo NA, da Silva Veiga LC, dos Reis PP, Nishimoto IN, Magrin J, Kowalski LP, et al. Classic and molecular cytogenetic analyses reveal chromosomal gains and losses correlated with survival in head and neck cancer patients. Clin Cancer Res. 2005;11:621-31.
20. Fringes B, Mayhew TM, Reith A, Gates J, Ward DC. Numerical aberrations of chromosomes 1 and 17 correlate with tumor site in human gastric carcinoma of the diffuse and intestinal types. Fluorescence in situ hybridization analysis on gastric biopsies. Lab Invest. 2000;80:1501-8.
21. Hes O, Síma R, Nemcová J, Hora M, Bulimbasic S, Kazakov DV, et al. End-stage kidney disease: gains of chromosomes 7 and 17 and loss of Y chromosome in non-neoplastic tissue. Virchows Arch. 2008;453:313-9.
22. Hardisson D, Álvarez-Marcos C, Salas-Bustamante A, Alonso-Guervós M, Sastre N, Sampedro A. Numerical aberrations of chromosomes 8, 9, 11, and 17 in squamous cell carcinoma of the pharynx and larynx: a fluorescence in situ hybridization and DNA flow cytometric analysis of 50 cases. Oral Oncol. 2004;40:409-17.
23. Gallucci M, Guadagni F, Marzano R, Leonardo C, Merola R, Sentinelli S, et al. Status of the p53, p16, RB1 and HER-2 genes and chromosomes 3, 7, 9, and 17 in advanced bladder cancer: correlation with adjacent mucosa and pathological parameters. J Clin Pathol. 2005;58:367-71.
24. Gotte K, Schafer C, Riedel F, Arens N, Hormann K. Intratumoral genomic heterogeneity in primary head and neck cancer and corresponding metastases detected by dual-FISH. Oncol Rep. 2004;11:17-23.
25. Risio M, Casorzoa L, Chiecchioa L, De Rosaa G, Rossinib F. Deletions of 17p are associated with transition from early to advanced colorectal cancer. Cancer Genet Cytogenet. 2003;147:44-9.
26. Gomyo Y, Osaki M, Kaibara N, Ito H. Numerical aberrations and point mutation of p53 gene in human gastric intestinal metaplasia and well-differenciated adenocarcinoma: analysis by fluorescence in situ hybridization (FISH) and PCR-SSCP. Int J Cancer. 1996;66:594-9.
27. Boveri T. Zur Frage der Entstehung maligner Tumoren. Jena: Gustar Fischer, Jena; 1914. p. 1-64.
28. Duesberg P, Li R, Rasnick D, Rausch C, Willer A, Kraemer A, et al. Aneuploidy precedes and segregates with chemical carcinogenesis. Cancer Genet Cytogenet. 2000;119:83-93.
29. Li L, McCormack AA, Nicholson JM, Fabarius A, Hehlmann R, Sachs RK, et al. Cancer-causing karyotypes: chromosomal equilibria between stabilizing aneuploidy and stabilizing selection for oncogenic function. Cancer Genet Cytogenet. 2009;188:1-25.
30. Kops GJ, Weaver BA, Cleveland DW. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer. 2005;5:773-85.
31. Michor F. Chromosomal instability and human cancer. Philos Trans R Soc Lond B Biol Sci. 2005;360:631-5.
32. Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature. 1997;386:623-7.
33. Liang Z, Zeng X, Gao J, Wu S, Wang P, Shi X, et al. Analysis of EGFR, HER, and TOP2A gene status and chromosomal polysomy in gastric adenocarcinoma from Chinese patients. BMC Cancer. 2008;8:363-72.
34. Reinholz MM, Bruzek AK, Visscher DW, Lingle WL, Schroeder MJ, Pérez EA, et al. Breast cancer and aneusomy 17: implications for carcinogenesis and therapeutic response. Lancet Oncol. 2009;10:267-77.
35. Takahasi Y, Nagata T, Asai S, Shintaku K, Eguchi T, Ishi Y, et al. Detection aberrations on 17p and gene in gastrointestinal cancers by dual (two-color) fluorescence in situ hybridization and GeneChip p53 assay. Cancer Genet Cytogenet. 2000;121:38-43.
36. Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J. Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol. 2009;27:1627-36.
37. Cesar AC, Borim AA, Caetano A, Cury PM, Silva AE. Aneuploidies, deletion, and overexpression of TP53 gene in intestinal metaplasia of patients without gastric cancer. Cancer Genet Cytogenet. 2004;153:127-32.
38. Veiga L, Bérgamo N, Kowalski L, Rogatto S. Classical and molecular cytogenetic analysis in head and neck squamous cell carcinomas. Genet Mol Biol. 2003;26:121-8.
39. Nahi H, Lehmann S, Bengtzen S, Jansson M, Möllgård L, Paul C, et al. Chromosomal aberrations in 17p predict in vitro drug resistance and short overall survival in acute myeloid leukemia. Leuk Lymphoma. 2008;49:508-16.
40. Fahmy M, Skacel M, Gramlich TL, Brainard JA, Rice TW, Goldblum JR, et al. Chromosomal gains and genomic loss of p53 and p16 genes in Barrett's esophagus detected by fluorescence in situ hybridization of cytology specimens. Mod Pathol. 2004;17:588-96.
41. Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer. 2001;1:157-62.42. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396:643-9.
43. Soussi T, Lozano G. p53 mutation heterogeneity in cancer. Biochem Biophys Res Commun. 2005;331:834-42.
44. Nowak MA, Michor F, Iwasa Y. Genetic instability and clonal expansion. J Theor Biol. 2006;241:26-32.
45. Yoshimura A, Sugihara H, Ling ZQ, Peng DF, Mukaisho K, Fujiyama Y, et al. How wild-type TP53 is inactivated in undifferentiated-type gastric carcinomas: analyses of intratumoral heterogeneity in deletion and mutation of TP53. Pathobiology. 2006;73:40-9.
46. Aguilera A, Gómez-González B. Genome instability: a mechanistic view of its causes and consequences. Nat Rev Genet. 2008;9:204-17.
47. Panani AD. Cytogenetic and molecular aspects of gastric cancer: clinical implications. Cancer Lett. 2008;266:99-115.
48. Montenegro Y, Ramírez-Castro JL , Isaza LF, Bedoya G, Muñetón-Peña CM. Análisis genético en pacientes con cáncer colorrectal. Rev Med Chil. 2006;134:1221-9.
49. Worthley DL, Whitehall VL, Spring KJ, Leggett BA. Colorectal carcinogenesis: road maps to cancer. World J Gastroenterol. 2007;13:3784-91.
Cómo citar
1.
Herrera JC, Isaza LF, Ramírez JL, Vásquez G, Muñetón CM. Detección de aneuploidías del cromosoma 17 y deleción del gen TP53 en una amplia variedad de tumores sólidos mediante hibridación in situ fluorescente bicolor. biomedica [Internet]. 30 de septiembre de 2010 [citado 20 de abril de 2024];30(3):390-40. Disponible en: https://revistabiomedica.org/index.php/biomedica/article/view/273
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