Predisposición hereditaria de padecer melanoma en familias uruguayas
Resultados preliminares
Palabras clave:
MELANOMA, SINDROMES NEOPLASICOS HEREDITARIOS, MUTACION, URUGUAYResumen
El melanoma cutáneo es el cáncer cuya incidencia presenta la mayor tasa de crecimiento en el mundo. Su tasa de mortalidad no ha disminuido pese a las terapias costosas empleadas para su diagnóstico y tratamiento. Puede presentarse bajo dos formas: esporádica y hereditaria. Esta última incluye a individuos con alto riesgo de desarrollar melanoma, variando su frecuencia según la población estudiada. El objetivo general del presente trabajo es contribuir al conocimiento de la predisposición hereditaria de padecer melanoma en Uruguay. Mediante la aplicación de un formulario de tamizaje se identificaron 14 familias con alto riesgo de padecer melanoma hereditario. Diecisiete pacientes integrantes de ellas dieron su consentimiento informado para investigar mutaciones de línea germinal en CDKN2A y CDK4. La detección de cambios genéticos se realizó mediante PCR-SSCP (Polymerase Chain Reaction - Single Stranded Conformational Polymorphism). Los fragmentos con un patrón de bandas de SSCP atípicos fueron analizados mediante secuenciación. Se identificaron dos mutaciones: una en el exón 2 de CDKN2A (E88X) en dos pacientes familiares de primer grado portadoras de melanomas múltiples y síndrome familiar de nevos atípicos (SFNA) y con historia familiar de melanoma y cáncer de páncreas. Esta mutación de línea germinal no ha sido descripta previamente en familias con melanoma. La otra mutación identificada (G101W) es una de las más frecuentes a nivel mundial. Ambas mutaciones fueron identificadas en pacientes con SFNA y múltiples melanomas en sus familias. La frecuencia de mutaciones encontrada concuerda con la documentada en estudios previos que utilizaron criterios de selección similares.
Citas
(1) Delgado L, Martínez M, Espasandín J, Priario J. Melanoma cutáneo. In: Musé I, Viola A, Sabini G. ed. Aspectos prácticos de la oncología clínica. Montevideo: Sudamericana, 2004: 381-95.
(2) Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999; 49: 8-31.
(3) Diepgen TL, Mahler V. The epidemiology of skin cancer. Br J Dermatol 2002; 146 (Suppl 61): 1-6.
(4) Barrios E, Vasallo J, De Stéfani E. Patterns of cutaneous malignant melanoma incidence and mortality in Uruguay. Melanoma Res 2001; 11(Suppl 1): S138.
(5) Priario J. Historia del melanoma maligno en Uruguay. Rev med Urug 2005; 21: 255-68.
(6) Kraehn M, Schartl M, Peter R. Human melanoma: a genetic disease? Cancer 1994; 75: 1228-37.
(7) MacKie RM. Incidence, risk factors and prevention of melanoma. Eur J Cancer 1998; 34 (Suppl 3): S3-S6.
(8) Greene M. The genetics of hereditary melanoma and nevi. 1998 update. Cancer 1999; 86: 2464-77.
(9) Goldstein AM, Tucker MA. Genetic epidemiology of familial melanoma. Dermatol Clin 1995; 13: 605-12.
(10) Aitken JF, Duffy DL, Green A, Youl P, MacLennan R, Martin NG. Heterogeneity of melanoma risk in families of melanoma patients. Am J Epidemiol 1994; 140:961-73.
(11) Slade J, Marghoob AA, Salopek TG, Rigel DS, Kopf AW, Bart RS. Atypical mole syndrome: risk factor for cutaneous malignant melanoma and implications for management. J Am Acad Dermatol 1995; 32: 479-94.
(12) Aitken J, Welch J, Duffy D, Milligan A, Green A, Martin N, et al. CDKN2A variants in a population-based sample of Queensland families with melanoma. J Natl Cancer Inst 1999; 91: 446-52.
(13) Holland EA, Schmid H, Kefford RF, Mann GJ. CDKN2A (P16(INK4a)) and CDK4 mutation analysis in 131 Australian melanoma probands: effect of family history and multiple primary melanomas. Genes Chromosomes Cancer 1999; 25: 339-48.
(14) Hashemi J, Platz A, Ueno T, Stierner U, Ringborg U, Hansson J. CDKN2A germ-line mutations in individuals with multiple cutaneous melanomas. Cancer Res 2000; 60: 6864-7.
(15) Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, et al. Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet 1998; 7: 209-16.
(16) Newton Bishop JA, Harland M, Bennett DC, Bataille V, Goldstein AM, Tucker MA, et al. Mutation testing in melanoma families: INK4A, CDK4 and INK4D. Br J Cancer 1999; 80: 295-300.
(17) Landi MT, Goldstein AM, Tsang S, Munroe D, Modi W, Ter-Minassian M, et al. Genetic susceptibility in familial melanoma from northeastern Italy. J Med Genet 2004; 41: 557-66.
(18) Fraser MC, Goldstein AM, Tucker MA. The genetics of melanoma. Semin Oncol Nurs 1997; 13: 108-14.
(19) Sauroja I, Smeds J, Vlaykova T, Kumar R, Talve L, Hahka-Kemppinen M, et al. Analysis of G(1)/S checkpoint regulators in metastatic melanoma. Genes Chromosomes Cancer 2000; 28: 404-14.
(20) Nam J. Interval estimation and significance testing for cyclic trends in seasonality studies. Biometrics 1995; 51: 1411-7.
(21) Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 1996; 12: 97-9.
(22) Cannon-Albright LA, Goldgar DE, Meyer LJ, Lewis CM, Anderson DE, Fountain JW, et al. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22. Science 1992; 258: 1148-52.
(23) Plna K, Hemminki K. Re: High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 2001; 93(4): 323-5.
(24) Borg A, Sandberg T, Nilsson K, Johannsson O, Klinker M, Masback A, et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 2000; 92: 1260-6.
(25) Lynch HT, Brand RE, Hogg D, Deters CA, Fusaro RM, Lynch JF, et al. Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer 2002; 94: 84-96.
(26) Goldstein AM, Chidambaram A, Halpern A, Holly EA, Guerry IV D, Sagebiel R, et al. Rarity of CDK4 germline mutations in familial melanoma. Melanoma Res 2002; 12: 51-5.
(27) Pollock PM, Stark MS, Palmer JM, Walters MK, Aitken JF, Martin NG, et al. Mutation analysis of the CDKN2A promoter in Australian melanoma families. Genes Chromosomes Cancer 2001; 32: 89-94.
(28) Aitken JF, Green A, MacLennan R, Jackman L, Martin NG. Comparability of surrogate and self-reported information on melanoma risk factors. Br J Cancer 1993; 67: 1036-41.
(29) Goldstein AM, Struewing JP, Chidambaram A, Fraser MC, Tucker MA. Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. J Natl Cancer Inst 2000; 92: 1006-10.
(30) Vasen HF, Gruis NA, Frants RR, van Der Velden PA, Hille ET, Bergman W. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16(p16-Leiden). Int J Cancer 2000; 87: 809-11.
(31) Battistutta D, Palmer J, Walters M, Walker G, Nancarrow D, Hayward N. Incidence of familial melanoma and MLM2 gene. Lancet 1994; 344: 1607-8.
(32) Laud K, Kannengiesser C, Avril MF, Chompret A, Stoppa-Lyonnet D, Desjardins L, et al. French Herediatary Melanoma Study Group. BRAF as a melanoma susceptibility candidate gene? Cancer Res 2003; 63: 3061-5.
(33) Meyer P, Klaes R, Schmitt C, Boettger MB, Garbe C. Exclusion of BRAFV599E as a melanoma susceptibility mutation. Int J Cancer 2003; 106: 78-80.
(34) de Snoo FA, Bergman W, Gruis NA. Familial melanoma: a complex disorder leading to controversy on DNA testing. Fam Cancer 2003; 2: 109-16.
(35) Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility. Adopted on February 20, 1996. J Clin Oncol 1996; 14: 1730-6.
(36) Tsao H, Niendorf K. Genetic testing in hereditary melanoma. J Am Acad Dermatol 2004; 51: 803-8.
(37) Marsh D, Zori R. Genetic insights into familial cancers: update and recent discoveries. Cancer Lett 2002; 181: 125-64.
(38) Ferrone CR, Ben Porat L, Panageas KS, Berwick M, Halpern AC, Patel A, et al. Clinicopathological features of and risk factors for multiple primary melanomas. JAMA 2005; 294: 1647-54.
(39) Puig S, Malvehy J, Badenas C, Ruiz A, Jimenez D, Cuellar F, et al. Role of the CDKN2A locus in patients with multiple primary melanomas. J Clin Oncol 2005; 23: 3043-51.
(40) Delgado L, Fernández G, González A, Bressac-de Paillerets B, Gualco G, Bombled J, et al. Hereditary breast cancer associated with a germline BRCA2 mutation in identical female twins with similar disease expression. Cancer Genet Cytogenet 2002; 133: 24-8.
(41) Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci USA 1989; 86: 2766-70.
(42) Ciotti P, Struewing JP, Mantelli M, Chompret A, Avril MF, Santi PL, et al. A single genetic origin for the G101W CDKN2A mutation in 20 melanoma-prone families. Am J Hum Genet 2000; 67: 311-9.
(43) Levanat S, Situm M, Crnic I, Marasovic D, Puizina-Ivic N, Pokupcic N, et al. Alterations in CDKN2A locus as potential indicator of melanoma predisposition in relatives of non-familial melanoma cases. Croat Med J 2003; 44: 418-24.
(44) Huber J, Ramos ES. The P48T germline mutation and polymorphism in the CDKN2A gene of patients with melanoma. Braz J Med Biol Res 2006; 39: 237-41.
(45) Eliason MJ, Larson AA, Florell SR, Zone JJ, Cannon-Albright LA, Samlowski WE, et al. Population-based prevalence of CDKN2A mutations in Utah melanoma families. J Invest Dermatol 2006; 126: 660-6.
(2) Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999; 49: 8-31.
(3) Diepgen TL, Mahler V. The epidemiology of skin cancer. Br J Dermatol 2002; 146 (Suppl 61): 1-6.
(4) Barrios E, Vasallo J, De Stéfani E. Patterns of cutaneous malignant melanoma incidence and mortality in Uruguay. Melanoma Res 2001; 11(Suppl 1): S138.
(5) Priario J. Historia del melanoma maligno en Uruguay. Rev med Urug 2005; 21: 255-68.
(6) Kraehn M, Schartl M, Peter R. Human melanoma: a genetic disease? Cancer 1994; 75: 1228-37.
(7) MacKie RM. Incidence, risk factors and prevention of melanoma. Eur J Cancer 1998; 34 (Suppl 3): S3-S6.
(8) Greene M. The genetics of hereditary melanoma and nevi. 1998 update. Cancer 1999; 86: 2464-77.
(9) Goldstein AM, Tucker MA. Genetic epidemiology of familial melanoma. Dermatol Clin 1995; 13: 605-12.
(10) Aitken JF, Duffy DL, Green A, Youl P, MacLennan R, Martin NG. Heterogeneity of melanoma risk in families of melanoma patients. Am J Epidemiol 1994; 140:961-73.
(11) Slade J, Marghoob AA, Salopek TG, Rigel DS, Kopf AW, Bart RS. Atypical mole syndrome: risk factor for cutaneous malignant melanoma and implications for management. J Am Acad Dermatol 1995; 32: 479-94.
(12) Aitken J, Welch J, Duffy D, Milligan A, Green A, Martin N, et al. CDKN2A variants in a population-based sample of Queensland families with melanoma. J Natl Cancer Inst 1999; 91: 446-52.
(13) Holland EA, Schmid H, Kefford RF, Mann GJ. CDKN2A (P16(INK4a)) and CDK4 mutation analysis in 131 Australian melanoma probands: effect of family history and multiple primary melanomas. Genes Chromosomes Cancer 1999; 25: 339-48.
(14) Hashemi J, Platz A, Ueno T, Stierner U, Ringborg U, Hansson J. CDKN2A germ-line mutations in individuals with multiple cutaneous melanomas. Cancer Res 2000; 60: 6864-7.
(15) Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, et al. Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet 1998; 7: 209-16.
(16) Newton Bishop JA, Harland M, Bennett DC, Bataille V, Goldstein AM, Tucker MA, et al. Mutation testing in melanoma families: INK4A, CDK4 and INK4D. Br J Cancer 1999; 80: 295-300.
(17) Landi MT, Goldstein AM, Tsang S, Munroe D, Modi W, Ter-Minassian M, et al. Genetic susceptibility in familial melanoma from northeastern Italy. J Med Genet 2004; 41: 557-66.
(18) Fraser MC, Goldstein AM, Tucker MA. The genetics of melanoma. Semin Oncol Nurs 1997; 13: 108-14.
(19) Sauroja I, Smeds J, Vlaykova T, Kumar R, Talve L, Hahka-Kemppinen M, et al. Analysis of G(1)/S checkpoint regulators in metastatic melanoma. Genes Chromosomes Cancer 2000; 28: 404-14.
(20) Nam J. Interval estimation and significance testing for cyclic trends in seasonality studies. Biometrics 1995; 51: 1411-7.
(21) Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 1996; 12: 97-9.
(22) Cannon-Albright LA, Goldgar DE, Meyer LJ, Lewis CM, Anderson DE, Fountain JW, et al. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22. Science 1992; 258: 1148-52.
(23) Plna K, Hemminki K. Re: High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 2001; 93(4): 323-5.
(24) Borg A, Sandberg T, Nilsson K, Johannsson O, Klinker M, Masback A, et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 2000; 92: 1260-6.
(25) Lynch HT, Brand RE, Hogg D, Deters CA, Fusaro RM, Lynch JF, et al. Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer 2002; 94: 84-96.
(26) Goldstein AM, Chidambaram A, Halpern A, Holly EA, Guerry IV D, Sagebiel R, et al. Rarity of CDK4 germline mutations in familial melanoma. Melanoma Res 2002; 12: 51-5.
(27) Pollock PM, Stark MS, Palmer JM, Walters MK, Aitken JF, Martin NG, et al. Mutation analysis of the CDKN2A promoter in Australian melanoma families. Genes Chromosomes Cancer 2001; 32: 89-94.
(28) Aitken JF, Green A, MacLennan R, Jackman L, Martin NG. Comparability of surrogate and self-reported information on melanoma risk factors. Br J Cancer 1993; 67: 1036-41.
(29) Goldstein AM, Struewing JP, Chidambaram A, Fraser MC, Tucker MA. Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. J Natl Cancer Inst 2000; 92: 1006-10.
(30) Vasen HF, Gruis NA, Frants RR, van Der Velden PA, Hille ET, Bergman W. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16(p16-Leiden). Int J Cancer 2000; 87: 809-11.
(31) Battistutta D, Palmer J, Walters M, Walker G, Nancarrow D, Hayward N. Incidence of familial melanoma and MLM2 gene. Lancet 1994; 344: 1607-8.
(32) Laud K, Kannengiesser C, Avril MF, Chompret A, Stoppa-Lyonnet D, Desjardins L, et al. French Herediatary Melanoma Study Group. BRAF as a melanoma susceptibility candidate gene? Cancer Res 2003; 63: 3061-5.
(33) Meyer P, Klaes R, Schmitt C, Boettger MB, Garbe C. Exclusion of BRAFV599E as a melanoma susceptibility mutation. Int J Cancer 2003; 106: 78-80.
(34) de Snoo FA, Bergman W, Gruis NA. Familial melanoma: a complex disorder leading to controversy on DNA testing. Fam Cancer 2003; 2: 109-16.
(35) Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility. Adopted on February 20, 1996. J Clin Oncol 1996; 14: 1730-6.
(36) Tsao H, Niendorf K. Genetic testing in hereditary melanoma. J Am Acad Dermatol 2004; 51: 803-8.
(37) Marsh D, Zori R. Genetic insights into familial cancers: update and recent discoveries. Cancer Lett 2002; 181: 125-64.
(38) Ferrone CR, Ben Porat L, Panageas KS, Berwick M, Halpern AC, Patel A, et al. Clinicopathological features of and risk factors for multiple primary melanomas. JAMA 2005; 294: 1647-54.
(39) Puig S, Malvehy J, Badenas C, Ruiz A, Jimenez D, Cuellar F, et al. Role of the CDKN2A locus in patients with multiple primary melanomas. J Clin Oncol 2005; 23: 3043-51.
(40) Delgado L, Fernández G, González A, Bressac-de Paillerets B, Gualco G, Bombled J, et al. Hereditary breast cancer associated with a germline BRCA2 mutation in identical female twins with similar disease expression. Cancer Genet Cytogenet 2002; 133: 24-8.
(41) Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci USA 1989; 86: 2766-70.
(42) Ciotti P, Struewing JP, Mantelli M, Chompret A, Avril MF, Santi PL, et al. A single genetic origin for the G101W CDKN2A mutation in 20 melanoma-prone families. Am J Hum Genet 2000; 67: 311-9.
(43) Levanat S, Situm M, Crnic I, Marasovic D, Puizina-Ivic N, Pokupcic N, et al. Alterations in CDKN2A locus as potential indicator of melanoma predisposition in relatives of non-familial melanoma cases. Croat Med J 2003; 44: 418-24.
(44) Huber J, Ramos ES. The P48T germline mutation and polymorphism in the CDKN2A gene of patients with melanoma. Braz J Med Biol Res 2006; 39: 237-41.
(45) Eliason MJ, Larson AA, Florell SR, Zone JJ, Cannon-Albright LA, Samlowski WE, et al. Population-based prevalence of CDKN2A mutations in Utah melanoma families. J Invest Dermatol 2006; 126: 660-6.
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Publicado
2007-06-30
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1.
Larre Borges García A, Scarone M, Delgado L, Núñez J, Laporte M, Fernández G, et al. Predisposición hereditaria de padecer melanoma en familias uruguayas: Resultados preliminares. Rev. Méd. Urug. [Internet]. 30 de junio de 2007 [citado 25 de noviembre de 2024];23(2):109-15. Disponible en: https://revista.rmu.org.uy/index.php/rmu/article/view/625
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