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Genetika primárnych mozgových nádorov.

Genetika primárnych mozgových nádorov. 1p / 19q status v oligodendrogliómoch MGMT status v glioblastómoch INI1 proteín v rabdoidných tumoroch. Oligodendrogliómy a 1p / 19q LOH. T1W. Oligodendrogliómy. odpoveď na PCV (1980, Levin et al.) súvis s 1p / 19q (1994, Reifenberg et al.).

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Genetika primárnych mozgových nádorov.

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  1. Genetika primárnych mozgových nádorov.

  2. 1p / 19q status v oligodendrogliómoch • MGMT status v glioblastómoch • INI1 proteín v rabdoidných tumoroch

  3. Oligodendrogliómy a 1p / 19q LOH. T1W

  4. Oligodendrogliómy • odpoveď na PCV (1980, Levin et al.) • súvis s 1p / 19q (1994, Reifenberg et al.)

  5. Metodiky • RFLP (restriction fragment length polymorphism) • PCR based microsatellite analysis • FISH • Quantitative PCR • CGH (comparative genomic hybridisation) • MLPA (multiplex ligation-dependent probe amplification – komerčné kity)

  6. 1p strata 1p/19q v priebehu ochorenia = strata chemosenzitivity • Washington University – od 1999 • Kramáre – leto 2006

  7. Dopad na liečbu? • 1p / 19q negat, LOH 10q, PTEN mutácia, EGFR amplifikácia – PCV terapia sa neodporúča (Ino et al.)

  8. Morfológia astro - like oligo - like

  9. MGMT a multiformný glioblastóm

  10. MGMT gén – na chromozóme 10q26 • metylácia MGMT promótera – epigenetický „silencing“

  11. Metodiky: • IHC • HPLC (high-performance liquid chromatography) • MSP (metylation sensitive PCR) – aj s parafínu, ale presnejšie z kryo

  12. Dopad na kliniku: • benefit alkylačnej chemoterapie – len u tumorov s metylovaným (silenced) promóterom pre MGMT • neexistuje alternatíva liečby !!!

  13. vyššie dávky temozolomidu?

  14. Atypical teratoid / rhabdoid tumor - expresia proteínu INI1

  15. Atypical teratoid / rhabdoid tumour (AT/RT) • agresívny embryonálny CNS tumor • pôvodne popísaný ako agresívny variant Wilmsovho tumoru s rabdomyosarkomatóznymi črtami

  16. hSNF5/INI1 gén lokalizovaný na 22q11.2 – supresorový gén pre AT/RT aj periférne rabdoidy • hSNF5/INI1 kóduje INI1 proteín z rodiny chromatín remodulujúceho komplexu (SWI/SFN) – regulácia transkripcie génov • AT/RT – rabdoidné elementy nemusia byť vyjadrené, imunofenotyp vysoko variabilný

  17. INI1 proteín • komerčne dostupná protilátka od 2004 • silná korelácia molekulárnych – cytogenetických a imunohistochemických znakov • AT/RT – zablokovanie expresie • ostatné CNS tumory – zachovaná expresia

  18. Meduloblastóm

  19. Biegel JA, Kalpana G, Knudsen ES, et al.: The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: meeting summary from the workshop on childhood atypical teratoid/rhabdoid tumors. Cancer Res 2002, 62:323-8 Diagnóza AT / RT • tumor má charakteristické morfologické a imunohistochemické črty AT/RT bez dokázanej mutácie INI1 • črty meduloblastóm / PNET s dokázanou INI 1 mutáciou

  20. SMARCB1/INI1 missense mutation in mucinous carcinoma with rhabdoid features Yong Mee Cho Jene Choi Ok-Jun Lee Hyang-Im Lee Duck Jong Han and Jae Y. Ro, pages 702–706, Pathology International, Volume 56 Issue 11 Page 702-706, November 2006

  21. 52. Loss of INI1 Expression Is Characteristic of Both Conventionaland Proximal-Type Epithelioid Sarcoma JL Hornick, P Dal Cm, COM Fletcher. Brigham and Women's Hospital. HarvardMedical School. Boston, MA.

  22. Záver: • microarray gene profilings are demonstrating that genetically-based prognosis may be more reliable than histologically-based prognosis (Nutt et al., 2003)

  23. Použitá literatúra: • 7th Congress of the European Association for Neurooncology (EANO), Postgraduate Course: Biomarkers and Therapy in Neurooncology, University Campus, Court 2, Lecture Hall CI, Spitalgasse 2, 1090 Vienna, Austria Thursday, September 14, 2006, 9.00-10.30 • MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma, Monika E. Hegi, Ph.D., Annie-Claire Diserens, M.Sc., Thierry Gorlia, M.Sc., N Engl J Med 352;10, march 10, 2005 • Allelic Losses at 1p36 and 19q13 in Gliomas: Correlation with Histologic Classification, Definition of a 150-kb Minimal Deleted Region on 1p36, and Evaluation of CAMTA1 as a Candidate Tumor Suppressor Gene, Violetta Barbashina,1 Paulo Salazar, Eric C. Holland, Marc K. Rosenblum and Marc Ladanyi, Clinical Cancer Research, Vol. 11, 1119– 1128, February 1, 2005 • Alterations of the hSNF5/INI1 Gene in Central Nervous System Atypical Teratoid/Rhabdoid Tumors and Renal and Extrarenal Rhabdoid Tumors, Jaclyn A. Biegel,2 Lu Tan, Fan Zhang, • Luanne Wainwright, Pierre Russo, and Lucy B. Rorke, Clinical Cancer Research, Vol. 8, 3461–3467, November 2002

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