Studi sull eziologia dei Tumori Cutanei: risultati, problemi prospettive

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1 Studi sull eziologia dei Tumori Cutanei: risultati, problemi prospettive CPO Registro Tumori Piemonte Stefano Rosso, Roberto Zanetti Riunione del Comitato Scientifico CPO, Torino, 3 ottobre 2008

2 Correva l anno 1982 Studio promosso da IARC e IACR: Descriptive epidemiology of malignant melanoma

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4 In quegli anni i primi studi caso-controllo sull eziologia del melanoma Klepp O, Magnus K. Some environmental and bodily characteristics of melanoma patients. A case-control study. Int J Cancer ; 23: Adam SA, Sheaves JK, Wright, Mosser G, arris RW, Vessey MP. A casecontrol study of the possible association between oral contraceptives and malignant melanoma. Br J Cancer. 1981; 44: MacKie RM, Aitchison T. Severe sunburn and subsequent risk of primary cutaneous malignant melanoma in Scotland. Br J Cancer. 1982; 46: Lew RA, Sober AJ, Cook, Marvell R, Fitzpatrick TB. Sun exposure habits in patients with cutaneous melanoma: a case control study. J Dermatol Surg Oncol. 1983; 9: Acquavella JF, Wilkinson GS, Tietjen GL, Key CR, Stebbings J, Voelz GL. A melanoma case-control study at the Los Alamos ational Laboratory. ealth Phys. 1983; 45: Beral V, Evans S, Shaw, Milton G. Cutaneous factors related to the risk of malignant melanoma. Br J Dermatol. 1983; 109:

5 e nel 1984 parte il nostro primo studio caso-controllo sull eziologia del melanoma

6 Gli studi di quegli anni olman CD, Armstrong BK. Cutaneous malignant melanoma and indicators of total accumulated exposure to the sun: an analysis separating histogenetic types. JCI 1984; 73: olman CD, Armstrong BK. Pigmentary traits, ethnic origin, benign nevi, and family history as risk factors for cutaneous malignant melanoma. JCI 1984; 72: Elwood JM, Gallagher RP, ill GB, Spinelli JJ, Pearson JC, Threlfall W. Pigmentation and skin reaction to sun as risk factors for cutaneous melanoma: Western Canada Melanoma Study. Br Med J (Clin Res Ed). 1984; 288: Beral V, Evans S, Shaw, Milton G. Oral contraceptive use and malignant melanoma in Australia. Br J Cancer. 1984; 50:

7 I nostri risultati Zanetti R, Rosso S, Colonna S, Martina G, Paudice A. Casecontrol study on malignant skin melanoma in the Turin province. G Ital Dermatol Venereol. 1988; 123: Zanetti R, Rosso S, Faggiano F, Roffino R, Colonna S, Martina G. A case-control study of melanoma of the skin in the province of Torino, Italy. Rev Epidemiol Sante Publique. 1988; 36: Zanetti R, Franceschi S, Rosso S, Bidoli E, Colonna S. Cutaneous malignant melanoma in females: the role of hormonal and reproductive factors. Int J Epidemiol. 1990; 19: Zanetti R, Franceschi S, Rosso S, Colonna S, Bidoli E. Cutaneous melanoma and sunburns in childhood in a southern European population. Eur J Cancer. 1992; 28A:

8 the role of hormonal and reproductive factors Karagas MR, Stukel TA, Dykes J, Miglionico J, Greene MA, Carey M, Armstrong B, Elwood JM, Gallagher RP, Green A, olly EA, Kirkpatrick CS, Mack T, Osterlind A, Rosso S, Swerdlow AJ. A pooled analysis of 10 casecontrol studies of melanoma and oral contraceptive use. Br J Cancer 2002; 86: Karagas MR, Zens MS, Stukel TA, Swerdlow AJ, Rosso S, Osterlind A, Mack T, Kirkpatrick C, olly EA, Green A, Gallagher R, Elwood JM, Armstrong BK. Pregnancy history and incidence of melanoma in women: a pooled analysis. Cancer Causes Control. 2006; 17: 11-9.

9 Cutaneous melanoma and sunburns in childhood Zanetti R. et al Rev Epidemiol Sante Publique: total number of weeks spent at beach during holidays in childhood is associated with an increased risk in men: OR=2.4( ) 3.7( ) Østerlind et al Int J Cancer: OR=3.7 ( )

10 Ipotesi dell esposizione intermittente al sole Armstrong BK. Epidemiology of malignant melanoma: intermittent or total accumulated exposure to the sun? J Dermatol Surg Oncol. 1988; 14: Zanetti R. et al Rev Epidemiol Sante Publique: The increased risk of intense and occasional sun exposure has been confirmed

11 Gli studi sui carcinomi cutanei Kricker A, Armstrong BK, English DR, eenan PJ (1991) Pigmentary and cutaneous risk factors for non-melanocytic skin cancer - a case-control study. Int J Cancer, 48: Gallagher RP, ill GB, Bajdic CD, Fincham S, Coldman AJ, McLean DI, Threlfall WJ (1995a) Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma. Arch Dermatol 131: Gallagher RP, ill GB, Bajdic CD, Fincham S, Coldman AJ, McLean DI, Threfall WJ (1995b) Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. II. Squamous cell carcinoma. Arch Dermatol 131:

12 Lo studio elios I sui carcinomi cutanei Studio multicentrico (Italia, Francia, Spagna, Svizzera) caso-controllo sui carcinomi cutanei sqamocellulari e basocellulari Reclutamento: BCC, 228 SCC, 1795 controlli

13 I nostri risultati sui carcinomi cutanei Zanetti R, Rosso S, Martinez C, avarro C, Schraub S, Sancho-Garnier, Franceschi S, Gafa L, Perea E, Tormo MJ, Laurent R, Schrameck C, Cristofolini M, Tumino R, Wechsler J. The multicentre south European study 'elios'. I: Skin characteristics and sunburns in basal cell and squamous cell carcinomas of the skin. Br J Cancer. 1996; 73: Rosso S, Zanetti R, Martinez C, Tormo MJ, Schraub S, Sancho-Garnier, Franceschi S, Gafa L, Perea E, avarro C, Laurent R, Schrameck C, Talamini R, Tumino R, Wechsler J. The multicentre south European study 'elios'. II: Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin. Br J Cancer. 1996; 73: Rosso S, Zanetti R, Pippione M, Sancho-Garnier. Parallel risk assessment of melanoma and basal cell carcinoma: skin characteristics and sun exposure. Melanoma Res. 1998; 8: Zanetti R, Gafa L, Franceschi S, Pippione M, Rosso S. Estimate of the proportion of skin tumors attributable to sun exposure in 3 Italian populations. Epidemiol Prev. 1999; 23: Rosso S, Joris F, Zanetti R. Risk of basal and squamous cell carcinomas of the skin in Sion, Switzerland: a case-control study. Tumori. 1999; 85: Suarez B, Lopez-Abente G, Martinez C, avarro C, Tormo MJ, Rosso S, Schraub S, Gafa L, Sancho- Garnier, Wechsler J, Zanetti R. Occupation and skin cancer: the results of the ELIOS-I multicenter case-control study. BMC Public ealth. 2007; 7: 180 Zanetti R, Rosso S, Martinez C, ieto A, Miranda A, Mercier M, Loria DI, Osterlind A, Greiner R, avarro C, Fabbrocini G, Barbera C, Rancho-Garnier, Gafa L, Chiarugi A, Mossoti R. Comparison of risk patterns in carcinoma and melanoma of the skin in men: a multi-centre case-case-control study. Br J Cancer. 2006; 94:

14 Meta-analisi sul melanoma Bliss JM, Ford D, Swerdlow AJ, et al. Risk of cutaneous melanoma associated with pigmentation characteristics and freckling: systematic overview of 10 case-control studies. The International Melanoma Analysis Group (IMAGE). Int J Cancer, 1995; 62: Elwood JM, Jopson J. Melanoma and sun exposure: an overview of published results. Int J Cancer. 1997; 73: Whiteman DC, Whiteman CA, Green AC. Childhood sun exposure as a risk factor for melanoma: a systematic review of epidemiologic studies. Cancer Causes Control, 2001; 12: Gandini S, Sera F, Cattaruzza MS, Pasquini P, Abeni D, Boyle P, Melchi CF. Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi. Eur J Cancer, 2005; 41: Gandini S, Sera F, Cattaruzza MS, Pasquini P, Picconi O, Boyle P, Melchi CF. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer, 2005; 41: Gandini S, Sera F, Cattaruzza MS, Pasquini P, Zanetti R, Masini C, Boyle P, Melchi CF. Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. Eur J Cancer. 2005; 41:

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16 LA curva dose-risposta Rosso, Zanetti, Pippione, Sancho-Garnier, Melanoma Res 1998; 8:

17 senza trascurare gli aspetti di metodologia della misura Wechsler J, Zanetti R, Schrameck C, Rosso S, Pippione M, Linares J, Laurent R, Ortuno G, Boi S, Gafa L, Joris F, Spatz A, Barneon G, Sacerdote C, Sancho-Garnier and the ELIOS Group. Reproducibility of histopathologic diagnosis and classification of non-melanocytic skin cancer: a panel exercise in the framework of the multicenter southern European study ELIOS. Tumori. 2001; 87: Rosso S, Minarro R, Schraub S, Tumino R, Franceschi S, Zanetti R. Reproducibility of skin characteristic measurements and reported sun exposure history. Int J Epidemiol. 2002; 31:

18 All inizio del millennio nuovi studi su markers biologici Studi su markers somatici del melanoma (es. BRAF), proto-oncogeni (es CDK2C) o polimorfismi (MC1R) Studi su marker biochimici: melanine

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20 Tyrosinase O COO O 2 O CO 2 O 2 O CO 2 O O O O O O DICA O O COO 2 O 2 O 2 Tyrosine DOPA Dopaquinone - + O Dopachrome EUMELAIS O Zn 2+ O O O O COO O O O DI O O O [O ] O O O COO -C O 2 CO 2 CO 2 CO 2 O O COO Leucodopachrome Zn 2+ O COO O COO O COO 2 S S S 2 CO 2 CO 2 O S O COO CO 2 ) 2 O S O S 2 COO COO COO 2 5-S -Cysteinyldopa S 2 O CO 2 O COO cysteinyldopa S S cysteinyldopa dopaquinone O 2 2 O O O 2 C 2 2 COO CO 2 O CO 2 S S S CO 2 2 COO PEOMELAIS and TRICOCROMES

21 IDETIFICATIO AD QUATITATIO OF MELAIS I PIGMETED TISSUES DEGRADATIVE APPROAC (degradation of pigmented tissue) Spectrophotometric analysis PLC analysis COMPLEMETARY APPROAC: In vitro reconstruction of the biosynthetic pathway

22 un lungo periodo trascorso ad affinare le metodiche d analisi Zanetti R, Prota G, apolitano A, Martinez C, Sancho-Garnier, Osterlind A, Sacerdote C, Rosso S. Development of an integrated method of skin phenotype measurement using the melanins. Melanoma Res. 2001; 11: Zoccola M, Mossoti R, Innocenti R, Loria DI, Rosso S, Zanetti R. ear infrared spectroscopy as a tool for the determination of eumelanin in human hair. Pigment Cell Res. 2004; 17: Zoccola M, Mossotti R, Innocenti R, Loria DI, Rosso S, Zanetti R. A new approach in the determination of eumelanin in human hair using near infrared spectroscopy. IR news : Zanetti R, Zoccola M, Mossotti R, Innocenti R, Loria DI, Rosso S; elios 2 Working Group. PTCA determination in human hair: reliability and analytical aspects. Med Sci Monit. 2006; 12: 23-8.

23 Studio elios 2 Studio multi-centrico (Italia, Francia, Spagna, Portogallo, Danimarca, Germania, Argentina) su BCC (215), SCC (139), CMM (214) e gruppo di controllo (349) Reclutamento: Determinazione delle melanine su campioni di capelli

24 Determinazione di eumelanine su campioni di capelli Materiali: 100 campioni di capelli di casi (melanoma) 100 campioni di capelli di controlli Le eumelanine nei campioni di capelli sono state ossidate con 2 O 2 e il marker strutturale quantitativo delle eumelanine, il PTCA, è stato determinato tramite PLC. Colonna: C18 Xterra (Waters) 30 C Eluente: 97% acido formico 0.4 M e sodio ottanosulfonato 0.5mM p 2.5, 3%metanolo, (vol/vol) Flusso : 0.7ml/min Detector: UV 270 nm I campioni di capelli (10 mg) sono stati immersi in ao 1 contenente 2 O 2 e lasciati reagire per 24 h, a 20 C sotto agitazione. La 2 O 2 residua è stata decomposta con aggiunta di a 2 S 2 O 5 la miscela è stata acidificata a p 4 e centrifugata. Il supernatante è stato filtrato e iniettato per analisi PLC.

25 Determinazione di PTCA su capelli tramite PLC Capelli rossi PTCA (ng/mg) Capelli rossi 30 Capelli biondi 50 Capelli biondi Capelli castani Capelli castani 100 Capelli neri Capelli neri La resa di PTCA è di circa il 6-7% a partire da DICA melanine Il PTCA deriva soprattutto da DICA unità delle melanine, e in bassa quantita da DI unità: In capelli di differente colore il rapporto DI/DICA non è costante. Profili cromatografici ottenuti dalla miscela di degradazione di quattro campioni di capelli di differente colore: capelli rossi, biondi, bruni e neri. PTCA è formato in bassa quantità da feomelanine ossidate con 2 O 2..

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27 Table 2. Risk of CMM for different levels and measurement scale of PTCA (eumelanin) in hair. In parenthesis 95% credible regions PAEL A Category of exposure for level of PTCA in ng/mg Case + Control - Case - Control + Crude OR Adj OR AdjOR FS 50 < ( ) ( ) ( ) ( ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) PAEL B Cut-off at 85 ng/mg Case + Control - Case - Control + Crude OR Adj OR AdjOR FS 85 < vs ( ) ( ) ( ) PAEL C Continuous scale Case < Control * Case > Control # Crude OR Adj OR AdjOR FS range ng/mg ( ) ( ) ( ) * number of pairs where PTCA levels were lower in cases # number of pairs where PTCA levels were lower in controls

28 Table 4. Risk of CMM for eumelanin in hair measured with IR (cut-off at 85 ng/mg) and corrected with calibration study. In parenthesis 95% credible regions umber of discordant pairs Case + Control - Case - Control Crude ORs Crude & Crude OR Corrected OR ( ) ( ) Adjusted by risk group strata* Adjusted & Adjusted OR Corrected OR ( ) ( ) * Four risk group strata from observed combinations of eye colour, number of naevi and hair colour

29 uman pigmentation-related genes Locus Protein Function Melanosome proteins TYR Tyrosinase Oxidation of tyrosine, dopa TYRP1 gp75, TRYP1 DICA-oxidase, TYR stabilisation DCT DCT, TRYP2 Dopachrome tautomerase SILV gp100, pmel17, Silver DICA-polymerisation and melanosome striations OCA2 P-protein p of melanosome and melanosome maturation MATP MATP, AIM-1 Melanosome maturation Signal proteins ASIP Agouti signal protein MC1R antagonist MC1R MS receptor G-protein coupled receptor POMC POMC, MS, ACT MC1R agonist OA1 OA1 protein G-protein coupled receptor MITF MITF Transcription factor Proteins involved in melanosome transport or uptake by keratinocytes MYO5A MyosinVa Motor protein RAB27A Rab27a RAS family protein PS1 PS1 Organelle biogenesis and size PS6 PS6 Organelle biogenesis

30 Estimates of population attributable fraction in different countries Germany/Denmark 43.9 France 26.4 Italy 17.8 Spain 13.6

31 Summary of results from the GEM study ucleotide excision repair genes XPD 312 (OR 1.5) XPD 751 (OR 1.4) Millikan et al 2006 CDK2A Berwick et al 2006 (OR 4.3 p<0.05) MC1R Dwyer et al 2003 (OR 1.4 ns) MC1R Kanetsky et al 2006 (OR 1.6 p<0.05) EGF G/G vs A/A (OR 1.09 ns) Amend et al 2004 IK4A (OR 7.2 ns) Berwick et al 2004

32 Sun Exposure Analysis Erythemal UV dose (age 10) SPM MPM OR unadj OR adj1 OR adj2 CDK2A (-) (controls) (cases) Low exposure (reference) 1.00 (reference) 1.00 (reference) igh exposure ( ) 1.62 ( ) 1.39 ( ) CDK2A (+) Low exposure (reference) 1.00 (reference) 1.00 (reference) igh exposure ( ) 1.25 ( ) 3.44 ( ) OR unadj : unadjusted ORs OR adj1 : Adjusted ORs - age, sex and age*sex interaction OR adj2 : Adjusted ORs - centre (7 centres), tan (4 levels), European ancestry, age, sex and age*sex interaction

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34 un nuovo filone di studi su melanoma, Parkinson e LevoDopa Zanetti R, Loria DI, Rosso S. Melanoma, Parkinson's disease and levodopa: causal or spurious link? A review of the literature. Melanoma Res. 2006; 16: Zanetti R, Rosso S Levodopa and risk of melanoma. Lancet. 2007; 369: Zanetti R, Rosso S, Loria DI. Parkinson s disease and cancer. Cancer Epidemiol Biomarkers Prev 2007; 16: 1081.

35 le nuove sfide Estensione delle analisi con metodica IR su melanine e carcinomi cutanei Studi congiunti sui marker biochimici e genetici Ruolo dell esposizione solare come fattore prognostico Studio di coorte su pazienti con Parkinson Dosimetria UV

36 Estensione delle analisi con metodica IR su melanine e carcinomi cutanei Progetto Ricerca Sanitaria Finalizzata bando 2007: Individuazione di gruppi ad alto rischio di tumore cutaneo: misurazione con metodo spettrofotometrico (nir) della eumelanina.

37 Studi congiunti sui marker biochimici e genetici uman pigmentation-related genes Locus Protein Function Melanosome proteins TYR Tyrosinase Oxidation of tyrosine, dopa TYRP1 gp75, TRYP1 DICA-oxidase, TYR stabilisation DCT DCT, TRYP2 Dopachrome tautomerase SILV gp100, pmel17, Silver DICA-polymerisation and melanosome striations OCA2 P-protein p of melanosome and melanosome maturation MATP MATP, AIM-1 Melanosome maturation Signal proteins ASIP Agouti signal protein MC1R antagonist MC1R MS receptor G-protein coupled receptor POMC POMC, MS, ACT MC1R agonist OA1 OA1 protein G-protein coupled receptor MITF MITF Transcription factor Proteins involved in melanosome transport or uptake by keratinocytes MYO5A MyosinVa Motor protein RAB27A Rab27a RAS family protein PS1 PS1 Organelle biogenesis and size PS6 PS6 Organelle biogenesis

38 Ruolo dell esposizione solare come fattore prognostico Rosso S, Sera F, Segnan, Zanetti R. Sun exposure prior to diagnosis is associated with improved survival in melanoma patients: Results from a long-term follow-up study of Italian patients. Eur J Cancer. 2008; 44: e di altri fattori che possono influenzare la prognosi dei melanomi: Studio GEM2: studio di follow-up di casi (MPM) e controlli (SPM)

39 Studio di coorte su pazienti con Parkinson Identificazione dei pazienti con Parkinson attraverso i sistemi informativi correnti (SDO e farmaceutica)

40 Dosimetria UV Progetto di Ricerca Sanitaria Finalizzata, bando Prevenzione dei Tumori Cutanei: Sviluppo di uno Strumento e di un Metodo per la Dosimetria individuale dell Esposizione a Radiazione Solare.