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¿Es hereditario el cáncer?

¿Es hereditario el cáncer?. Javier Benítez Dpto. Genética Humana CNIO . Cancer incidence in spain (Cases /year). Location Male Female Total. Lung 13.728 1.362 15.090 Colorectal 7.770 6.842 14.632 Breast 12.598 12.598

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¿Es hereditario el cáncer?

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  1. ¿Es hereditario el cáncer? Javier Benítez Dpto. Genética Humana CNIO

  2. Cancer incidence in spain (Cases /year) Location Male Female Total Lung 13.728 1.362 15.090 Colorectal 7.770 6.842 14.632 Breast 12.598 12.598 Stomach 4.849 3.026 7.875 Bladder 6.685 1.134 7.819 Prostate 5.394 5.394 From IARC 2.000

  3. Cáncer esporádico Cáncer familiar

  4. ¿ Por qué es importante el asesoramiento genético? • 5% de los cánceres pueden ser hereditarios • Implicaciones sociales, familiares, individuales • Importante la identificación y selección de familias a riesgo para: - Asesorar - Estudiar - Prevenir

  5. 46 cromosomas31.000 genes3.000 millones de bases

  6. A A T T C C G G Adenina (A) Citosina (C) T C A T G A C G Siemprese une a Siempre se une a Guanina (G) Timina (T) G C Ser Stop Arg Proteína

  7. Gen #1 Gen #2 Gen #3 Un Gene es un segmento de DNA que da lugar a una proteína. Colágeno Anticuerpo Insulina

  8. La variación genética contribuye a las diferencias interindividuales. PERO, cambios en genes críticos dan lugar a mutaciones

  9. ATGCAGAGGTCGCCTCTGGAAAAGGCCAGCGTTGTCTCCAAACTTTTTTTCAGCTGG CCAGACCAATTTTGAGGAAAGGATACAGACAGCGCCTGGAATTGTCAGACATATACC AATCCCTTCTGTTGATTCTGCTGACAATCTATCTGAAAAATTGGAAAGAGAATGGGA AGAGAGCTGGCTTCAAAGAAAAATCCTAAACTCATTAATGCCCTTCGGCGATGTTTT TCTGGAGATTTATGTTCTATGGAATCTTTTTATATTTAGGGGAAGTCACCAAAGCAG ACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGACCCGGATAACAAGGAGGA CGCTCTATCGCGATTTATCTAGGCATAGGCTTATGCCTTCTCTTTATTGTGAGGACA TGCTCCTACACCCAGCCATTTTTGGCCTTCATCACATTGGAATGCAGATGAGAATAG TATGTTTAGTTTGATTTATAAGAAGACTTTAAAGCTGTCAAGCCGTGTTCTAGATAA ATAAGTATTGGACAACTTGTTAGTCTCCTTTCCAACAACCTGAACAAATTTGATGAA GACTTGCATTGGCACATTTCGTGTGGATCGCTCCTTTGCAAGTGGCACTCCTCATGG GCTAATCTGGGAGTTGTTACAGGCGTCTGCCTTCTGTGGACTTGGTTTCCTGATAGT CTTGCCCTTTTTCAGGCTGGGCTAGGGAGAATGATGATGAAGTACAGAGATCAGAGA CTGGGAAGATCAGTGAAAGACTTGTGATTACCTCAGAAATGATTGAAAATATCCAAT TGTTAAGGCATACTGCTGGGAAGAAGCAATGGAAAAAATGATTGAAAACTTAAGACA ACAGAACTGAAACTGACTCGGAAGGCAGCCTATGTGAGATACTTCAATAGCTCAGCC TCTTCTTCTCAGGGTTCTTTGTGGTGTTTTTATCTGTGCTTCCCTATGCACTAATCA AGGAATCATCCTCCGGAAAATATTCACCACCATCTCATTCTGCATTGTTCTGCGCAT GCGGTCACTCGGCAATTTCCCTGGGCTGTACAAACATGGTATGACTCTCTTGGAGCA TAAACAAAATACAGGATTTCTTACAAAAGCAAGAATATAAGACATTGGAATATAACT AACGACTACAGAAGTAGTGATGGAGAATGTAACAGCCTTCTGGGAGGAGGGATTTGG GAATTATTTGAGAAAGCAAAACAAAACAATAACAATAGAAAAACTTCTAATGGTGAT ACAGCCTCTTCTTCAGTAATTTCTCACTTCTTGGTACTCCTGTCCTGAAAGATATTA TTTCAAGATAGAAAGAGGACAGTTGTTGGCGGTTGCTGGATCCACTGGAGCAGGCAA ACTTCACTTCTAATGATGATTATGGGAGAACTGGAGCCTTCAGAGGGTAAAATTAAG ACAGTGGAAGAATTTCATTCTGTTCTCAGTTTTCCTGGATTATGCCTGGCACCATTA AGAAAATATCAT TGGTGTTTCCTATGATGAATATAGATACAGAAGCGTCATCAA GCATGCCAACTAGAAGAGGACATCTCCAAGTTTGCAGAGAAAGACAATATAGTTCTT GAGAAGGTGGAATCACACTGAGTGGAGGTCAACGAGCAAGAATTTCTTTAGCAAGAG AGTATACAAAGATGCTGATTTGTATTTATTAGACTCTCCTTTTGGATACCTAGATGT TTAACAGAAAAAGAAATATTTGAAAGCTGTGTCTGTAAACTGATGGCTAACAAAACT GGATTTTGGTCACTTCTAAAATGGAACATTTAAAGAAAGCTGACAAAATATTAATTT GCATGAAGGTAGCAGCTATTTTTATGGGACATTTTCAGAACTCCAAAATCTACAGCC GACTTTAGCTCAAAACTCATGGGATGTGATTCTTTCGACCAATTTAGTGCAGAAAGA GAAATTCAATCCTAACTGAGACCTTACACCGTTTCTCATTAGAAGGAGATGCTCCTG CTCCTGGACAGAAACAAAAAAACAATCTTTTAAACAGACTGGAGAGTTTGGGGAAAA AGGAAGAATTCTATTCTCAATCCAATCAACTCTATACGAAAATTTTCCATTGTGCAA AGACTCCCTTACAAATGAATGGCATCGAAGAGGATTCTGATGAGCCTTTAGAGAGAA GCTGTCCTTAGTACCAGATTCTGAGCAGGGAGAGGCGATACTGCCTCGCATCAGCGT ATCAGCACTGGCCCCACGCTTCAGGCACGAAGGAGGCAGTCTGTCCTGAACCTGATG CACACTCAGTTAACCAAGGTCAGAACATTCACCGAAAGACAACAGCATCCACACGAA AGTGTCACTGGCCCCTCAGGCAAACTTGACTGAACTGGATATATATTCAAGAAGGTT Cáncer de mama: La población Judía presenta una deleción de dos bases (del185AG) en un alto porcentaje

  10. Cancer Mama - BRCA1/2 normal: 10% probabilidad de desarrollar la enfermedad - BRCA1/2 mutación: 80% probabilidad de desarrollar la enfermedad

  11. + - 1.5 millones de nucleotidos delecionados en Neurofibromatosis

  12. 6 ó más manchas café con leche Múltiples neurofribromas Nodulos de Lisch en iris

  13. Genes identificados Enfermedad Gen Año Cromosoma Retinoblastoma Rb 86 13 T. Wilms WT 90 11 Neurofibromatosis NF1 90 17 FAC poliposis APC 91 5 S. Li-Fraumeni P53 91 17 E. Tuberosa ET 94 16 Ca. Mama BRCA1 96 13 BRCA2 97 17 MEN1 MEN1 97 11 Ca. Gástrico CDH1 98 16 S. Cowden PTEN 99 10 Feocromocitoma SDHD 00 11 SDHC 01 1

  14. Cáncer familiar • Alrededor de un 5% de los cánceres • Edad temprana de aparición • Afectación de órganos pares/multifocalidad • Acumulo de un mismo tipo de cáncer en la familia

  15. Hereditary cancer-example

  16. Benefits of the genetic test • Identification of carriers • Rationalise clinical exploration • Design of new strategies for early detection and follow-up

  17. Limitation and application of the genetic test • Technical limitations • Meaning of a positive /negative result • Psychological impact • Information privacy • Clinical management

  18. ? ? ? Li-Fraumeni syndrome Gullet Ca. 51y. Breast cancer 22y. Pleural Mesotelioma 34y. Astrocytoma 33y. Osteosarcoma 17y. ? ? ? Bilateral colobome 4y. P53 carrier Non carrier

  19. ASYMPTOMATIC + CMT TGC618TTC CMT & PHEOCHROMOCYTOMA THYROID? GOITER 50 76 77 72 79 76 40 51 45 57 41 43 + + + + + + + - - + + + - - + - - - + - 34 32 22 34 20

  20. Family with hereditary breast cancer 35a. 35a. 46a. 30a.

  21. Familial breast cancer • About 10% of women will develop breast cancer • 5% will be hereditary • BRCA 1/2 are the responsible genes • The identification of these families is important for GC

  22. High risk for other cancers: • Bilateral Br. 50% • Ov. 30% • Prostate 20% • Others Genetic counseling • 25% high risk families associated to BRCAs • Variable penetrance: • 60-80% for Br. • 20-30% for Ov. • 10% for males

  23. Surveillance in at risk women • Annual mamography and clinical examination around 35 • years old • Surgery: • - Oophorectomy Breast cancer (50%) • - Mastectomy Breast cancer (90%) • - Contralateral breast surgery: 5 years better than 10 • years since the first Br Ca (12% vs 40%) • Oral contraceptives Ovarian risk • (TMX) BRCA + ??

  24. Hereditary nonpolyposis colorectal cancer(HNPCC) Accounts for 5% - 10% of all bowel cancers Autosomal dominant Penetrance as high as 85% - 90% Colon cancer at young mean age of 45y. 70% right sided cancers

  25. Colorectal cancer • Colonoscopy: from 20-25 years/every 2 or 3 years • Ca125 (endometrium): from 30-35y/every 1 or 2 years • Gastroscopy: from 30-35 y/every 1 or 2 years

  26. SCF sin genes conocidos o con modelo de herencia desconocido • Cáncer familiar • Ca páncreas • Ca testículo • Ca pulmón • Ca próstata* • Ca renal células claras • E.Hodgkin

  27. Cáncer renal de células claras (RCC) hereditario t(3;8) t(3;8) t(3;8) t(3;8) CN CN CN t(3;8) CN CN t(3;8) t(3;8) t(3;8) CN Cariotipo normal C. Mama Linfoma RCC células claras t(3;8) CN CN RCC papilar Nódulo renal benigno ?

  28. Dx.71a Ca. Mama bilateral Dx. 60 a Ca. Laringe Dx. 20 a Ca. Faringe Dx. 80 a Ca. Mama Dx. 63 a Ca. Próstata Dx. 60 a Ca. Pulmón Dx. 36 a Ca. Testiculo RM Ceguera Dx. 42 a Ca. mama 40 a Agregación familiar

  29. Dx. 72 a Ca. Mama (45-55) Múltiples cánceres • 48 a Melanoma • 53 a Ca. Colon • 55 a Ca. Tiroides • 59 a Ca. Mama

  30. Conclusiones • Un 5-10% del cáncer es familiar • Es importante conocer si el probandus pertenece a una familia a riesgo • Es importante realizar estudios predictivos • Se puede evitar el desarrollo de un tumor.

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