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National Cancer Advisory Board Genome-wide Association Studies

National Cancer Advisory Board Genome-wide Association Studies. Stephen Chanock, M.D. Chief, Laboratory of Translational Genomics, DCEG, NCI Director, Core Genotyping Facility, DCEG, NCI December 9, 2008. Milestones in Human Genomics & Disease Susceptibility. Achievements. Overall Impact.

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National Cancer Advisory Board Genome-wide Association Studies

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  1. National Cancer Advisory BoardGenome-wide Association Studies Stephen Chanock, M.D. Chief, Laboratory of Translational Genomics, DCEG, NCI Director, Core Genotyping Facility, DCEG, NCI December 9,2008

  2. Milestones in Human Genomics & Disease Susceptibility Achievements Overall Impact Human Genome Project Human Reference International HapMap Project Annotation of Common Genetic Variation Assemble Dense Markers for Association/Linkage Conduct Association & Linkage Studies Assess: Copy number of changes, expression profiling Robust genomic analysis technologies Genome-wide Association Studies with Replication Identify and Confirm Regions for Further Studies

  3. Basic Principle of Genetic Association Studies In Unrelated Individuals

  4. Genetic Association Testing:Finding Markers

  5. 10 million SNPs across the genome Areas of linkage disequilibrium across the genome Selection of tagSNPs to capture common genetic variation in population under study Genome wide SNP chips Association with disease risk in discovery and replication studies Mapping of susceptibility loci Garcia-Closas and Chanock in Clin Can Res 2009

  6. Promise of Genome-wide Association Studies • Discovery of New Regions in the Genome Associated with Diseases/Traits • New “Candidate Genes” • Explore genes/pathways • Etiology • Gene-Environment/Lifestyle Interactions • “Druggable” targets • Establish utility of genetic markers for risk prediction • For individual or public health decisions

  7. 2007 second quarter 2007 third quarter 2007 first quarter 2007 fourth quarter 2006 First quarter 2008 2005 Manolio, Brooks, Collins, J. Clin. Invest., May 2008

  8. Identifying Genetic Markers for Prostate & Breast Cancer • Genome-Wide Analysis • Public Health Problem Prostate (1 in 8 Men) Breast (1 in 9 Women) Analyze Long-Term Studies • NCI PLCO Study • Nurses’ Health Study Initial Study Follow-up #1 Follow-up #2 Establish Loci Fine Mapping Functional Studies Validate Plausible Variants Possible Clinical Testing http://cgems.cancer.gov

  9. Prostate Cancer Risk2006 • Age • Ethnic Background • Family History

  10. General Strategy for CGEMS Prostate GWAS circa 2006 Studies Initial Study 1150 cases/1150 controls 540,000 Tag SNPs PLCO ACS/ATBC/ HPFS/FrCC/ PHS* MEC/EPIC/ JHU/SwCaP/ CONOR Follow-up Study #1 4000 cases/ 4000 controls >28,000 SNPs Follow-up Study #2 5500 cases/ 5500 controls at least7,600 SNPs ~20 loci Fine Mapping Determine Causal Variant(s)

  11. Chanock S, Manolio T, et al, Nature 2007; 447:655-660.

  12. CGEMS Prostate Cancer GWAS 22 X 9 10 11 12 13 14 15 16 17 18 19 20 21 p q p q -2 Chromosomes 1 2 3 4 5 6 7 8 p q p q -2 -4 8q24 -6 Log10(p-value) -4 -6 incidence density sampling

  13. MSMB, b-microseminoproteinChromosome 10 • Encodes MSP of the immunoglobulin binding factor family • 10.7 kDa non-glycosylated cysteine rich protein • Synthesized by epidethilium of prostate • Secreted into seminal plasma • MSP and binding protein, PSPBP -- potential serum markers for early detection of high grade prostate cancer (Bjartell et al Clin Can Res 2007; Reeves et al Clin Can Res 2006; Nam et al J Urol 2006) • Silenced by EZH2 in advanced, androgen-insensitive prostate cancer (Beke et al Oncogene 2007) • “Best hit” rs10993994 -- promoter SNP alters gene expression in vitro(Buckland et al Hum Mut 2005)

  14. LD at MSMB – 15 SNPs tag this ~130kb region

  15. Association results, 6479 prostate cancer cases, ~6105 controls Yeager et al. in submission 2008

  16. 3.2 10-7 X 11 10 9 8 7 6 5 4 3 2 1 22 21 Y 20 19 17 18 16 15 14 13 12 16+ published loci involved in prostate cancer susceptibility with significance p < 5 x 10-7 2 10-9 4 10-13 9 10-29 7 10-13 2 10-12 2 10-9 8 10-9 3 10-8 1 10-9 1.7 10-7 6 10-10 3 10-19 6 10-18 3 10-17 1 10-18 3 10-15 7 10-12 9 10-14 Diabetes Type 2 1 10-12 1 10-9 2 10-18 3 10-10 KLK3 Eeles et al. 2008 Gudmundsson et al 2008 Haiman et al 2007 Prostate Specific Antigen

  17. Prostate Cancer Risk2008 • Age • Ethnic Background • Family History • Genetic markers • 16 Regions of the Genome!!!

  18. CGEMS – Cancer Genetic Markers of Susceptibility General Strategy for Breast Cancer GWAS Initial Study 1145 cases/1142 controls 540,000 Tag SNPs NHS WHI/ACS PLCO/PBSC2 NHS2/WHS/ PBSC2/USRT/ CONOR Follow-up Study #1 4500 cases/ 4500 controls >30,000 SNPs Follow-up Study #2 (A=21 and B=171) 4500 cases/ 4500 controls 192 SNPs >10 loci Fine Mapping

  19. FGFR2 Signals in GWAS: Intron 2 123.2 123.3 123.4 -4 log10(p-value) -2 0 FGFR2 Replicated NHS2, ACS, PLCO Cases/controls 2,921/3,214 Pooled: p 1.1 x 10-10 Hunter et al Nat Genet 2007

  20. Inherited Susceptibility to Breast Cancer ? Genes, environment

  21. Genetic Predisposition to Breast CancerEuropean population 10 BRCA1 BRCA2 TP53 PTEN CHEK2 ATM 3 PALB2 BRIP1 1.5 ??????? Population genotype relative risk 1.4 1.3 1.2 1.1 1 1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 5p12 5q11.2 16q12.1 8q24 10q26 2q35 Population risk-allele frequency

  22. Susceptibility Loci Modified by Estrogen Receptor Status 2.00 1.74 1.49 1.33 1.28 1.27 1.24 1.16 1.18 1.11 1.07 1.06 0.98 Ref. Ref. Ref. Genotypes 38% 47% 14% 53% 39% 8% 52% 40% 8% Frequency FGFR2 TNRC9 8q24 Gene Garcia-Closas et al. PLoS Genetics 2008

  23. Cancer susceptibility loci in the 8q24 region Colorectal Adenoma Prostate region 3 p = 7 x10-12 Thomas et al. Prostate region 2 p = 1 x10-18 Haiman et al. p = 1 x10-8 Gudmundsson et al. Prostate region 1 p = 3x 10-19 Thomas et al. Breast region p = 5 x10-12 Easton et al. Colon region p = 7x 10-11 Tomlinson et al. MYC 30 kb 231 Kb 58 Kb 126 Kb 209 Kb Bladder Cancer p= 9.34 x 10-12 Kiemeney et al 2008 rs6983267 rs16901979 rs13281615 rs4242382 rs1447295

  24. Replication and Mapping ‘Saturation’ Begin Functional Analyses Clarke et al AJHG 2007

  25. Prostate Cancer & 8q24 Rs1447295 replication in BPC3 & 3 Other Studies Commonly Amplified in Prostate tumors “Gene-poor region” GWAS- multiple signals Yeager et al Nat Genet 39:645-649, 2007 -log10 r2

  26. 454 Quality Control and genetic analyses • Concordance with GWAS data (for 79 PLCO samples), 39 SNPs, >99% per locus and per sample • Genotype calls for 791 SNPs

  27. Resequence analysis: Discovery of ALL Variants Further Genotyping to Nominate Best SNPs for Functional Analysis Yeager et al 2008

  28. Refining Linkage Disequilibrium across 2 Regions of 8q24 rs4242382 rs6983267 +2 SNPs highly correlated with rs6983267 +43 SNPs & 2 indels highly correlated with rs4242382

  29. Initial observations on 8q24 Prostate Cancer Susceptibility • All common (> 1% MAF) variants identified within 136 kb region • Two SNPs highly correlated with rs6983267 • Associated with prostate, colon, ovarian cancers • 43 SNPs and 2 indels highly correlated with rs4242382 • Associated with prostate cancer in Caucasian men • Each of these variants is equally as likely to be responsible for disease as the initially-reported SNPs

  30. rs6983267 – possible candidate for causal/contributory variant VISTA Enhancer prediction Regulatory potential Mammalian conservation

  31. Nominating Variants for Functional Analysis: Refining the GWAS and Replication 80 % of genome (r2 > 0.8) >500,000 SNPs Stage 1 Pinpoint Best Variants Genome-Wide Scan Stage 2 ~7000 regions ~30,000 SNPs Follow-up 1 ~10 000 genotyped case/control pairs (20 000 DNAs) Stage 3 ~150 regions ~7500 SNPs Follow-up 2 Saturation Genotyping Based on Resequence Analysis ~15 to 20 Established Loci

  32. DCEG CGEMS Breast cancer Prostate cancer PanScan I & II Lung cancer Bladder cancer Kidney cancer NHL Upper GI Gastric cancer Esophageal cancer Collaborative BPC3 Aggressive prostate cancer ER (-) breast cancer Brain tumor Testicular African American Prostate cancer Breast cancer GWAS at NCI

  33. Established prior to Meta-Analysis in Colorectal Cancer • 8q24 • Also Prostate Region 3 • Colorectal Adenoma • 8q23.3 (EIF3H) • 10p14 • 11q23 • 15q13 • 18q21 (SMAD7) • New Loci • 14q22 (BMP4) • 16q22.1 (CDH1) • 19q13.1 (RHPN2) • 20p12.3

  34. Novel GWAS Findings in Cancer • Lung • 15q24/25.1 (smoking behavior) • 5p15.33 (TERT or CLPTM1L) • 6p21.33 • Melanoma • 20q11.22 (ASIP, also basal cell carcinoma) • 11q14-q21 (TYR, also basal cell carcinoma) • Neuroblastoma • 6q22

  35. GWAS Studies:Just the Start…… “This is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.” Sir Winston Churchill @ Lord Mayor's Luncheon, Mansion House following the victory atEl AlameininNorth Africa London,10 November 1942.

  36. Next Steps? • Mapping Loci (>45 in cancer alone) • Identify “best variants” for biological investigation • Functional Analysis of Variants • Provide plausibility • Explore pathways • New GWAS Needed for Outcomes • So far, etiology and outcome have very little overlap • Different regions drive cancer progression • GWAS for Etiology in Comparable Environmental Exposures • Role of gene-environment interaction(s)

  37. Assessing GWAS Findings • Risk Assessment- • What Constitutes Suitable Reporting of Data • Absolute Risk vs. Relative Risk • Pharmacogenomics • New GWAS Studies • Value for Public Health and Personal Decisions • Consider New and Old Paradigms • Capitalize on Available Studies • Biospecimens on ALL current and new studies

  38. Acknowledgements HSPH Peter Kraft David Cox Sue Hankinson Fred Schumacher PLCO Chris Berg E David Crawford Catherine McCarty WHI Ross Prentice Rebecca Jackson Charles Kooperberg Rowan Chlebowski PBCS Jolanta Lissowska Beata Peplonska ACS Michael Thun Heather Feigelson Eugenia Calle Ryan Diver CeRePP, France Olivier Cussenot Geraldine Cancel-Tassin Antoine Valeri NPHI, Finland Jarmo Virtamo • CGEMS & DCEG • Gilles Thomas • Robert Hoover • David Hunter • Richard Hayes • Joseph Fraumeni • Daniela Gerhard • Demetrios Albanes • Kevin Jacobs • Meredith Yeager • Sholom Wacholder • Nilanjan Chatterjee • Zhaoming Wang • Xiang Deng • Nick Orr • Regina Ziegler • Kai Yu • Margaret Tucker • Jesus Gonzalez Bosquet • Montse Garcia-Closas Wash. U., St Louis Gerald Andriole Adam Kybell

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