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GENETICS OF MELANOMA

GENETICS OF MELANOMA. Ivana Antigoni Genetica Medica “Sapienza – Università di Roma” Ospedale S. Camillo. Kidney cancer and melanoma: progresses in clinical and translational research Rome, November 23-24, 2007. Genetic susceptibility to Melanoma.

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GENETICS OF MELANOMA

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  1. GENETICS OF MELANOMA Ivana Antigoni Genetica Medica “Sapienza – Università di Roma” Ospedale S. Camillo Kidney cancer and melanoma: progresses in clinical and translational research Rome, November 23-24, 2007

  2. Genetic susceptibility to Melanoma 5-10% of individuals who develop melanoma show an affected close relative Susceptibility to melanoma is inherited as an autosomal dominant trait, with a incomplete penetrance

  3. Clinical risk factors for Melanoma

  4. Genetics of melanoma Several genes are involved in the progression of cutaneous melanoma Two major groups of genes: 1. PROTO-ONCOGENES 2. TUMOR SUPPRESSOR GENES

  5. 1. Proto-oncogenes * MAPK PATHWAY (Mitogen-Activated Protein Kinase)

  6. CDK4 (12q13) Proto-oncogene Cyclin Dependent Kinases (promotes cell cycle progression from G1 to S phase) Action: phosphorylation of Rb1 Same pathway of p16 (functionally antagonist)

  7. BRAF (7q34) MAPK PATHWAY: BRAF/NRAS/HRAS2/HRAS BRAF mutations have been identified in more than 60% of melanomas and 80% of these occur at a single site (hot spot) in position 600 (V600E) Growth factor receptors interaction with its ligands induces Ras activation Ras activation stimulates phosphorylation of RAF proteins (including BRAF) The final step of this cascade (MEK/ERK/CCND1/Cdk4-6) is the activation of transcription factors (G1/S) Frequency of BRAF mutations in melanocytic nevi is similar to that in melanomas suggesting that BRAF function inactivation could be an “early event” from healty skin to nevi

  8. MAPK PATHWAY In contrast to BRAF mutations, NRAS alterations are more common in sun-exposed areas HRAS mutations are less commonly observed and occurs in no more than 1.5-3% of melanomas Activating changes in KRAS2 have been observed in rare cases and often associated with other Ras genes mutations

  9. Tumor Suppressor Genes

  10. CDKN2A/p14ARF (9p21) Coding exons: 3 (ex 1, 125 bp; ex 2, 307 bp; ex 3, 12 bp) Encodes two distinct proteins:INK4A (p16), ARF (p14) (alternative promoters and first exons: 1α, 1ß)

  11. CDKN2A/p14ARF (1) INK4A (p16):cell cycle G1/S progression specific inhibitor. Inhibits complex CDKs/cyclin D through competitive binding to Cdks 4/6 p14ARF: inactivation of HDM2 which inhibits p53, by binding and degradation (apoptosis inhibition)

  12. The chromosome region in which this gene maps is deleted in about 30-50% of melanomas • Somatic PTEN mutations have been identified in approximately 3% of primary melanomas and 8% of metastatic melanomas PTEN (10q23.31) TP53 (17p13.1) • Mutations in melanomas are rare (7%) • However, UVR is very likely the cause of these mutations, as well as in other non-melanocytic skin tumors

  13. CDKN2A germline mutations in familial melanoma • Identified in 15-20% of melanoma-prone families (at least two affected first or second degree relatives) • Present in 9-15 % of sporadic multiple primary melanomas (MPM) • Penetrance of 53% by age 80 • Interaction with sunlight exposure • High frequency of multiple primary melanomas (MPM), pancreatic and larynx cancer

  14. MC1R polymorphisms (16q24.3) MC1R (melanocortin-1 receptor) has been identified as a low-risk melanoma-susceptibility gene Variants of the MC1R are major determinants of high-risk phenotypes (red hair and pale skin) and of the ability to tan in response to UV exposure (RR: 1 variant = 2-5; 2 variant = 7) Some MCR1 polymorphisms could act as modifier alleles, able to increase CDKN2A mutations penetrance

  15. FAMILIAL MELANOMA (FM) MULTIPLE PRIMARY MELANOMAS (MPM) FAMILIAL MULTIPLE MELANOMA (FAMMM) 156 ITALIAN MELANOMA PEDIGREES 97 FM (22 FAMMM) 59 Sporadic Multiple Primary Melanomas (MPM) MOLECULAR ANALYSIS CDKN2A (sequencing analysis of exon 1 α, 1 ß, 2, 3 and exon-intron boundaries) CDKN2A (Multiple Ligation Probe Amplification) CDK4 (sequencing analysis of exon 2)

  16. * new mutation

  17. FM/MPM/FAMMM 17/156 (10,8%) CDKN2A MUTATION ------------------- 12,3% FM/FAMMM 6,8% MPM 9 DIFFERENT MUTATIONS 6 Gly101Trp PEDIGREES 1 PZ: COMPOUND HETEROZYGOTE 1 PZ:INTRONIC MUTATION

  18. Female, 38 y.o., familiar origin: Avezzano (Central Italy) March 1988: removal of 2 melanomas from deltoid region March 1998: removal of 1 melanoma from right haunch May 1998: removal of 5 melanomas December 2001: removal of relapsing melanoma (right haunch) Absence of family history for melanoma Father deceased for lung carcinoma CDKN2A Compound Heterozygote Asp105Glu/Asn71Ile

  19. Man, 49 y.o., familiar origin: Velletri (Central Italy), type II skin, blu eyes, more than 50 melanocytic nevi,8 primary melanomas (at 37),absence of family history for melanoma 1 son with IVS2-105 A>G/+ (follow-up) CDKN2A: IVS2-105 A>G Majore et al., Journal of Investigative Dermatology 122 (2), 450-451, 2004

  20. IVS2-105A>G 6 English families (same haplotype) Our patient: “de novo” variant Different haplotype from English pedigrees IVS2-105 mutation “hot-spot”

  21. Multiple Ligation Probe Amplification (MLPA) 90 PEDIGREES (CDKN2A negative) analysed: absence of deletions/duplications

  22. CDKN2A 1β (p14ARF): worldwide mutations Locus Base Nr of geneal. Origin g.192 A>T 1 UK g.193 G>C 1 UK g.193+1 G>A 1 Netherland g.193+2 T>C 1 USA g.193+3 A>G 1 UK g.193+56 T>C 2 UK Harland et al., Oncogene 24: 4604-4608, 2005 Mutation Nr of geneal. Origin del ex 1ß 1 UK ins 16 bp 1 Spain Rizos et al., 2001; Randerson-Moor et al., 2001

  23. 66/136 pedigrees CDKN2A negative g.193+1 G>A (2 families) CDKN2A/p14ARF: exon 1β

  24. Female patient, 20 y.o., red hair, green eyes, type II skin, UV burns 1992: removal of 1 melanoma from dorsum 1995: removal of 1 melanoma from trunk 1995: removal of 1 melanoma from dorsum 2002: removal of 1 melanoma from arm 1990: right haunch dysplastic nevi 1990: trunk dysplastic nevi 1991: trunk dysplastic nevi LAST FOLLOW-UP 27-03-2007: Disease free

  25. Pz. S. Gallicano Rome/Univ. Catanzaro: Familial origin: Rome/S. Vito Romano > 70 > 70 45/62 72 64 4 2 2 MPM 20 35 30/34 g.193+1 G>A g.193+1 G>A MELANOMA MPM: MULTIPLE PRIMARY MELANOMAS

  26. Pz S. Gallicano Rome – familial origin: Rome g.193+1 G>A 61 g.193+1 G>A WT WT WT 66 64 59 40/54 WT MELANOMA

  27. CDK4 CDKN2A/p14Arf NEGATIVE PEDIGREES (134) (sequencing analysis of exon 2 CDK4 gene) 7 FM pedigrees with mutations in CDK4 (codon 24) described worldwide 2 French (Arg24His) 2 USA (Arg24Cys) 1 Norvegian (Arg24His) 1 Australian (Arg24His) 1 English (Arg24His) 1 Italian (Arg24His)

  28. epatic carcinoma CDK4: Arg24His 41 trunk melanoma melanoma 59 45 Arg24His melanoma MPM Arg24His 41 38 Arg24His 19 (follow-up) Arg24His Melanoma Gastric carcinoma

  29. CDK4 HAPLOTYPE (microsatellite) Majore et al. Pigm Cell α Mel Res, in press.

  30. CDK4 Mutations are rare (8 cases) High expressivity 100% penetrance (?) No founder effect

  31. FAMILIAL MELANOMA (FM, FAMMM), MULTIPLE PRIMARY MELANOMA (MPM) 17/156 (10,8%) CDKN2A MUTATIONS 12,3% FM, FMMM 6,8% MPM 9DIFFERENT MUTATIONS 1 PZ: COMPOUND HETEROZYGOTE 3 NEW MUTATIONS CDKN2A EXON 1β: 2 FAMILIES: g.193+1 G>A CDK4 1 FAMILY: Arg24His 20/156: 12.8%

  32. UOC LABORATORIO DI GENETICA MEDICA, “SAPIENZA” UNIVERSITA’ DI ROMA, A.O. S. CAMILLO-FORLANINI, ROMA Francesco Binni, Carmelilia De Bernardo, Silvia Majore, Alessandra Crisi, Ivana Antigoni, Paola Grammatico UOSD DERMATOLOGIA OSP. S. CAMILLO, ROMA Giovanni Cruciani Genetics of Melanoma DERMATOLOGIA UNIVERSITA’ DI CATANZARO Ugo Bottoni POLICLINICO MILITARE CELIO DI ROMA Tiziana Sbezzi UOC DERMATOLOGIA ONCOLOGICA S. GALLICANO, IFO, ROMA Paola De Simone, Laura Eibenschutz, Caterina Catricalà

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