Pathologic prognosticators, primary tumor
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2 Pathologic prognosticators, primary tumor Epidermal invasion Ulceration (AJCC2009) BRESLOW (<1mm 1-2mm 2-4mm >4mm) Dermal invasion (Clark) Radial or Vertical Growth Satellite nodule= in-transit metastasis
3 % N stádium E T 10 year survival (T) according to N stages 10 year survival according to thickness of the primary % 10 probability éves halálozás of death (%) tumor vastagság (mm)
4 Superficial spreading UV Nodular UV CSD: chronic sun damage (solar keratosis) Intermittent sun exposure Acrolentiginous Mucosal Uveal non-uv non-uv UV?
5 UV-induced: BRAF mutation (or N-RAS) Non-UV: c-kit mutation Hereditary: p16 mutation CDKN2A oncosuppressor
6 wt B-Raf /Sanger sequencing: Sens: 15% c.1799t>a (V600E) c.1798_1799delgtinsaa (V600K) c.1798_1799delgtinsag (V600R) c.1799_1800deltginsaa (V600E)
7 N=341 9% 37% V600E Classical 54% wt V600E other Vemurafenib Dabrafenib 3% 3% 3% 16% 2.3% 7% 3% 5.9% 65% c.1789_1790delctinstc (L597S) c.1798_1799delgtinsaa (V600K) c.1798_1799delgtinsag (V600R) c.1798_1799delgtinsag (V600R) c.1799_1800deltginsaa (V600E) c.1801a>g (K601E) SU-2P Dabrafenib c.1841 C>G p.s614c
8 RAS exon Kodon eset % KRAS/NRAS melanoma KRASex2 kodon kodon other exon KRASex3 kodon kodon other exon KRASex4 kodon kodon other exon NRASex2 kodon kodon other exon NRASex3 kodon kodon % other exon NRASex4 kodon kodon other exon cases (n) Colombino et al. J Transl Med 11: 202,2013
9 Exon 11 (juxtamembranous): EC deletion TK-domain EC Exon 13 TKmut: sensitising Ex 9/17/18-mut: GLEEVEC RES
10 categories Histological SSM NM LMM AM AM LMM dpm nemm bnm cgnm MuM UM Molecular (mutated) BRAF (50%) N-RAS (20%) KIT (20%) MITF (20%) GRIN2A (30%) PTEN (30%) PI3K AKT CDKN2A (50%) CDK4 p53 (20%) BCL2 KIT (40%) GNAQ GNA11 Pathway 1.Growth factor receptor 1.b. MAPK 1.Growth factor receptor 1.b. MAPK 1.c PI3K 1.Growth factor receptor 3. MITF 2.G-protein coupled receptor NMDA 1.Growth factor receptor 4. Cell cycle 1a. KIT 2a. GRIN2A 1.c. PI3K 4a. CDKN2A 4b.CDK 5. apoptosis 1.Growth factor receptor 5a. p53 5b.BCL2 2.Gprotein coupled receptor MCR1 1a. KIT 2b. GNAQ, GNA11 SSM NM ALM UM
11 MC1R GRIN2A (NMDAR) KIT (EGFR) Cell surface (MET) GNAQ,GNA11 CDK CDKN2A nucleus MITF N-RAS B-RAF MAPK p53 PI3K AKT mtor PTEN Genetic defects of signaling pathways in melanoma
12 Melanosomal markers?: HMB45/pmel16, DCT, TRP1, tyrosinase, Mart1 (non-specific) Melanoma antigens?: NSE, TA90, NG2, MAGE3 Novel markers: p107rbl, CCND1/E1, RyanodinR2 (Deli et al. Int J Cancer 2007)
13 Cep6, RREB(c6), MYB(c6), CCND1(c11) multiplex FISH, Spec95.4%, sens 86.6% Options: (cell population levels) >19%CCND1 >2 or >55%RREB1 more than cep6 or >40% MYB less than cep6 or >16% RREB1 >2 Gerami et al. Arch Pathol Lab med 135:830,2011
14 DTIC/Temozolomide: MGMT, p16 mutation (Bush et al. Eur j Cancer 2010) Melphalan, ACMD: mp16, mbraf (Gallagher et al. Neoplasia, 2008) Chemoresistance: MSH6, XRCC1, ERCC1, MGMT (DNArepair) PI3K, mtor, ki67, TS, HSP90, SOD1 (Jewell et al. Clin Cancer Res 2010)
15 IRE-negative genes (fold difference > 6) IRE-positive genes (fold difference >2) upregulated b-cam AchR-E LamR RPP1 SB-IIAgA GPCRHG38 Ig-LCh JM1 HLA-III ALP p38pi3k RIG-E IF9-27 MxB p27/kip1 downregulated YKT6 PRL-1 PDK1 CL-100 STAM2 AML1b GalK HSP70B INGL1 VEGF IGFRS1 MGSA TGFb IRE: interferon responsive element in promoter
16 B-RAF mutation (positive) Vemurafenib resistance: N-RAS mutation, MEK1C21S, c-raf, MAP3K8/COT (Johannessen et al. Nature, 2011) HER2, AXL, PDGFRboverexpression, ERBB4, FLT1, PTPRD, RET, TERT, RUNX1T1 mutations (Wagle et al. JCO 2011)
17 MC1R GRIN2A (NMDAR) KIT (EGFR) Cell surface (MET) GNAQ,GNA11 CDK CDKN2A nucleus MITF N-RAS B-RAF MAPK p53 PI3K AKT mtor PTEN Genetic defects of signaling pathways in melanoma
18 TIL is heterogenous CD4+T(with CD25-IL2R, CD134) density is positive predictor (Ladanyi et al. Clin Canc Res 2004) DC-LAMP density is a positive predictor (Ladanyi et al. Can Immunol Immunother,2007) B-cell density is a positive independent prognosticator (Ladanyi et al. POR 2012) FOXP3+ T-reg densitiy is neutral (Ladanyi et al. POR,2010) Macrophage density (?): sex-dependent (Kiss et al. POR,2007)
19 Anti-CTLA4/ipilimumab: no predictive factor Anti-PD1/anti-PDL1: Nivolimumab: Melanoma-PDL1+ (IHC)
20 Morphology over molecular classification or vica versa. Metastatic versus non-metastatic melanoma: Prognosticator, stratificator? Melanoma immunology: lessons learned? Immunotherapy: predictions..
21 This work was supported by TAMOP 4.2.1B.-09/1/KMR Rásó E PhD Győrffy B MD PhD Barbai T phd student
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