CÉLINE MELIS ASSISTENT PATHOLOGISCHE ONTLEEDKUNDE PROMOTOR: PROF. DR. J.J. VAN DEN OORD Rol van WHSC1 in de progressie van cutane maligne melanomen.

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1 CÉLINE MELIS ASSISTENT PATHOLOGISCHE ONTLEEDKUNDE PROMOTOR: PROF. DR. J.J. VAN DEN OORD Rol van WHSC1 in de progressie van cutane maligne melanomen

2 2007 Elsevier. Fletcher: Diagnostic Histopathology of Tumors

3 Tumor progression: the process whereby tumours go from bad to worse. (L. Foulds)

4 Winnepenninckx V. Gene Expression Profiling of CMM 254 genen met prognostische waarde Correlatie met Breslow dikte  WHSC1

5 Wat is er al geweten over WHSC1?

6 Wolf-Hirschhorn syndrome Homozygote deletie 4p Microcephalie Hypertelorisme Greek warrior helmet Laagstaande oren Psychomotore retardatie Voedingsproblemen Epilepsie Foto: Linford S. Wolf-Hirschhorn syndrome. Medical genetics.[Online] 3. Kassambara A, et al. 2009 4. Antonius T. 2010

7 WHSC1 = histon methyltransferase Adcock IM et al. Respir Res 2006 10

8 Relatie met tumor progressie Multiple myeloma: associatie met slechtere prognose 5,6 Overexpressie in borstkanker, glioblastoom, GI tractus, blaaskanker, enz. 7 Associatie met tumor progressie o.a. in  Prostaatcarcinoom 5,10  Blaascarcinoom 3 3. Kassambara A, et al. Biochem Biophys Res Commun. 2009 5. Asangani IA, et al. Mol Cell. 2013 6. Lauring J, et al. Blood. 2008 7. Hudlebusch HR, et al. Clin Cancer Res. 2011 10. Adcock IM, et al. Respir Res. 2006.

9 Relatie met tumor progressie (vervolg) Lindgren et al. Oncogene 2006

10 Huidig onderzoeksproject: Rol van WHSC1 in de progressie van cutane maligne melanomen EXPRESSIEPATROON VAN WHSC1 IN CUTANE MALIGNE MELANOMEN IMMUUNHISTOCHEMIE RT-PCR

11 Immuunhistochemie (vervolg) Totaal PCMM = 23

12 Immuunhistochemie (vervolg) Scoresysteem Aantal positieve cellen (meest positieve deel)  0+geen enkele  1+< 25 %  2+≥ 25 %, < 50%  3+≥ 50 %

13 Immuunhistochemie: maligne weefsel PCMM, verticale groeifase (3+) PCMM, radiale groeifase (3+)

14 Immuunhistochemie: maligne weefsel PCMM, verticale groeifase (A 1+) PCMM, radiale groeifase (A 1+)

15 Immuunhistochemie: maligne weefsel Metastase (A 3+)

16 Immuunhistochemie: benigne weefsel Naevus (A 0+)

17 Immuunhistochemie: resultaten p < 0,001 p = 0,011

18 Immuunhistochemie: resultaten

19

20 q RT-PCR (PhD J. Wouters)

21 Blik op de toekomst Immuunhistochemie In vitro: maligne melanoom cellijnen In vivo: muizen met melanomen

22 Bronnen 1)Winnepenninckx V. Gene expression profiling of cutaneous malignant melanoma. België (Leuven); 2006. 2)Garbe C, Peris K, Hauschild A, et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – Update 2012. Eur J Cancer. 2012 Oct; 48(15):2375-90. 3)Kassambara A, Klein B, Moreaux J. MMSET is overexpressed in cancers: link with tumor aggressiveness. Biochem Biophys Res Commun. 2009 Feb 20; 379(4):840-5. 4)Online presentatie WHS 5)Asangani IA, Ateeq B, Cao Q, et al. Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer. Mol Cell. 2013 Jan 10; 49(1):80-93. 6)Lauring J, Abukhdeir AM, Konishi H, et al. The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood. 2008 Jan 15; 111(2):856-64. 7)Hudlebusch HR, Santoni-Rugiu E, Simon R, et al. The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. Clin Cancer Res. 2011 May 1; 17(9):2919-33. 8)Boek biochemistry 9)Ezponda T, Popovic R, Shah MY, et al. The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial-mesenchymal transition and invasive properties of prostate cancer. Oncogene. 2013 Jun 6; 32(23):2882-90. 10)Adcock IM, Ford P, Ito K, Barnes PJ. Epigenetics and airways disease. Respir Res. 2006 Feb 6; 7:21. 11)Martinez-Garcia E, Popovic R, Min DJ, et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood. 2011 Jan 6; 117(1):211-20. 12)Yang P, Guo L, Duan ZJ, et al. Histone methyltransferase NSD2/MMSET mediates constitutive NF-kB signaling for cancer cell proliferation, survival, and tumor growth via a feed-forward loop. Mol Cell Biol. 2012 Aug; 32(15):3121-31. 13)Kuo AJ, Cheung P, Chen K, et al. NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol Cell. 2011 Nov 18; 44(4):609-20. 14)Hudlebusch HR, Skotte J, Santoni-Rugiu, et al. MMSET is highly expressed and associated with aggressiveness in neuroblastoma. Cancer Res. 2011; 71:4226-4235.