Genetika%20prim

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• Genetika primárnych mozgových nádorov.

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

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Oligodendrogliómy a 1p / 19q LOH.
T1W
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Oligodendrogliómy

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

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Metodiky

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

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1p
strata 1p/19q v priebehu ochorenia strata
chemosenzitivity

• Washington University od 1999
• Kramáre leto 2006

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Dopad na liecbu?

• 1p / 19q negat, LOH 10q, PTEN mutácia, EGFR
  amplifikácia PCV terapia sa neodporúca (Ino et
  al.)

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Morfológia
astro - like
oligo - like
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MGMT a multiformný glioblastóm
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• MGMT gén na chromozóme 10q26
• metylácia MGMT promótera epigenetický
  silencing

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Metodiky

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

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Dopad na kliniku

• benefit alkylacnej chemoterapie len u tumorov s
  metylovaným (silenced) promóterom pre MGMT
• neexistuje alternatíva liecby !!!

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• vyššie dávky temozolomidu?

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Atypical teratoid / rhabdoid tumor - expresia
proteínu INI1
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Atypical teratoid / rhabdoid tumour (AT/RT)

• agresívny embryonálny CNS tumor
• pôvodne popísaný ako agresívny variant Wilmsovho
  tumoru s rabdomyosarkomatóznymi crtami

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• 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 byt vyjadrené,
  imunofenotyp vysoko variabilný

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INI1 proteín

• komercne dostupná protilátka od 2004
• silná korelácia molekulárnych cytogenetických a
  imunohistochemických znakov
• AT/RT zablokovanie expresie
• ostatné CNS tumory zachovaná expresia

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Meduloblastóm
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• 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,
  62323-8

Diagnóza AT / RT

1. tumor má charakteristické morfologické a
   imunohistochemické crty AT/RT bez dokázanej
   mutácie INI1
2. crty meduloblastóm / PNET s dokázanou INI 1
   mutáciou

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• 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 702706, Pathology
  International, Volume 56 Issue 11 Page 702-706,
  November 2006

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

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

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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 35210, 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,
  34613467, November 2002