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Genetic Variants and Melanoma Risk Simon N. Stacey

Genetic Variants and Melanoma Risk Simon N. Stacey. SNPs and Association Studies:. Freq SNP-A in Cases / Freq SNP-A in Controls ~ Risk of Disease with SNP-A / Risk of Disease without SNP-A ~ Relative Risk (RR) or Odds Ratio (OR). A A GGTTA to A T GGTTA . Marker of Predisposition

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Genetic Variants and Melanoma Risk Simon N. Stacey

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  1. Genetic Variants and Melanoma Risk Simon N. Stacey

  2. SNPs and Association Studies: Freq SNP-A in Cases / Freq SNP-A in Controls ~ Risk of Disease with SNP-A / Risk of Disease without SNP-A ~ Relative Risk (RR) or Odds Ratio (OR) AAGGTTA to ATGGTTA Marker of Predisposition Location, Location, Location

  3. Themes of large scale SNP association studies in melanoma : • Searching for melanoma variants among: • Genes affecting variation in pigmentation in Europeans • Genes affecting nevus counts • Genes affecting related cancers: Basal Cell Carcinoma (BCC) • Genes directly associated with melanoma risk • Rare variants detected by large scale sequencing • Multiple Testing in Genome Wide Association Studies • Bonferroni adjusted threshold for genome-wide significance: • 300,000 SNPs is 1.7 x 10-7 • 1M SNPs is 5 x 10-8 • 5M SNPs is 1 x 10-8

  4. Genetic variants that affect pigmentation traits in Europeans

  5. Using pigmentation to detect cancer loci: chr20 ASIP locus:

  6. ASIP Melanoma risk variants in MC1R pathway: Pigmentation-associated variants in MC1R, ASIP and Tyrosinase loci confer risk of both Melanoma and BCC

  7. Variants affecting nevus count confer risk of melanoma: Loci near CDKN2A and PLA2G6 (22p13) implicated

  8. Do variants that confer risk of BCC also confer risk of melanoma? BCC variant in TERT-CLPTM1L associated with lung, bladder, prostate cancer Variants in CDKN2A/B are also associated with melanoma, breast cancer, NPC and glioma

  9. BCC and multi-cancer TERT variant is protective against melanoma: • Related to the different roles of senescence and genome stability in melanocyte and keratinocyte transformation?

  10. GWAS directly for melanoma associated variants: • Bishop et al. 2009 Nature Genetics 41, 920-925 • Amos et al. 2011 Human Molecular Genetics 20, 5012-5023 • MacGregor 2011 Nature Genetics 43, 1114-1118 • Barrett et al 2011 Nature Genetics 43, 1108-1113 • Majority of variants are associated with known risk factors • Effect on risk factors often does not fully account for effect of variant on melanoma • Some pigmentation variants do not appear to be associated with melanoma risk • Increasing number of variants have no discernable effect on pigmentation • Variants are common and with modest effects

  11. Search for rare variants through genome sequencing: TA Manolioet al. Nature461, 747-753 (2009) doi:10.1038/nature08494

  12. High power is required to detect association of rare variants: • Shows OR required to detect variants to P= 2x10-9 at 80% power • Bonferroni GWS for 30M variants • Rare variants need large effects and/or large sample sizes to detect by association • Sequence data from large numbers of people are required • Integrated approach using both statistical and biological data is required

  13. Icelandic Sequencing Project: • Whole genome sequencing of 1,800 Icelanders • Average coverage 18x • Identified 23 million SNPs and 8 million short indels and added functional annotation • Used as a training set to impute genotypes of 72,000 SNP phased, chip-typed Icelanders • Phasing and imputation allows us to carry out case:control associations studies based on full-resolution genomic sequence data (i.e. 30 million variants)

  14. Icelandic Sequencing Project discovers BCC variant in TP53:

  15. Icelandic Sequencing Project results for MITF E318K: • Bertolotto et al 2011 Nature and Yokoyama et al 2011 Nature reported variant E318K in MITF in familial and sporadic melanoma • Integrated association and biological data • Investigated in Icelandic sequencing project data and replication cohorts:

  16. Collaborators: • deCODE Genetics • Patrick Sulem • Gisli Masson • Daniel F. Gudbjartsson • Thorunn Rafnar • Sigurjón Axel Guðjónsson • Guðmar Þorleifsson • Augustine Kong • Unnur Thorsteinsdottir • Kari Stefansson • National University Hospital Iceland • Jon H. Olafsson • BardurSigurgeirsson • Kristrun R. Benediktsdottir • Kristin Thorisdottir • RafnRagnarsson • KarolinskaInstitutet • Johan Hansson • Annika Lindblom • Comprehensive Cancer Centre and Radboud University Medical Centre Nijmegen • Lambertus A. Kiemeney • KatjaAben • DKFZ Heidelberg Group • Rajiv Kumar • University Hospital Zaragoza • José I. Mayordomo • Instituto Valenciano de Oncologica, Valencia • Eduardo Nagore • Fondazione IRCCS Istituto Nazionale Tumori, Milan • Monica Roldolfo • Licia Rivoltini • Medical University of Vienna • Ichiro Okamoto • Hubert Pehamberger • Judith Wendt

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