cancer genetic markers of susceptibility...0 aggressive cancer 0 737 non-aggressive cancer 624...
TRANSCRIPT
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Cancer Genetic Markers of Susceptibility
Stephen J Chanock, M.D. November 29, 2006
http://cgems.cancer.gov
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Mission of CGEMS
Conduct genome-wide SNP scans in Prostate cancer (1 in 8 men) Breast cancer (1 in 9 women) Analyze and publish findings
Rapid sequential replication studies Aggressive timeline Initial scan in nested case-control studies from
Prostate, Lung, Colon, Ovary (PLCO) Project Nurses’ Health Study
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Replication Strategy for Prostate Cancer
Initial Study 1150 cases/1150 controls >500,000 Tag SNPs
Replication Study #1
3000 cases/ 3000 controls
Replication Study #2
2400 cases/ 2400 controls
Replication Study #3
2500 cases/ 2500 controls
~24,000 SNPs
~1,500 SNPs
200+ New ht-SNPs
25-50 Loci
Fin e
ly m
appe
d ha
plot
ypes
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Power of the first two phases of CGEMS Point wise significance 10-7 ; "genome wide" significance 0.05
1
Power
0.8
0.6
0.4
AdditiveGRR : 1.4
0.10 0.2 0.3 0.4 0.5
Minor Allele Frequency
Recessive GRR : 2
Dominant GRR : 1.5
Multiplicative GRR : 1.3
0.2
0
GRR AA Aa aa
Recessive 2.0 1.0 1.0 2.0
Dominant 1.5 1.0 1.5 1.5 Continuous line : power for direct detection (r2 = 1) Additive 1.4 1.0 1.4 1.8 Dashed line : power for r2 = 0.8
Multiplicative 1.3 1.0 1.3 1.69 Skol et al. Nat Genet (2006)
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CGEMS Scans
Prostate Cancer Breast Cancer T
Two Scans One Scan Illumina Illumina
317k 240k 550k (available) (Feb 2007)
(March 2007)
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Recruitment Incidence Density SamplingNb. of selections
1st medic. end 1st end 2nd end 3rd end 4th end 5th
Rec
ruitm
ent f
rom
1 c
ente
r
random selection of 5 controls amongthese
random selection of 1 controls amongthese
random selection of 2 controls amongthese
random selection of 3 controls amongthese
random selection of 2 controls amongthese
5 pairs of 1 pair of 2 pairs of 3 pairs of 2 pairs of 3 pairs of prevalent incident incident incident incident incident
cases/controls case/control case/control case/control case/control case/control
1
1 1
1 2
2
2 1
2 1 1
1
as asexamination period period period period period control case
1111111111111111
16 pairs of case/control
25 DNAs to type
5 periods 6 strata
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Aggressive Prostate Cancer
• High priority to examine early vs aggressive• Cohort based studies (screening)
– Bias towards early cases • Enrich primary scan with >55%
aggressive:45% early – Aggressive defined as:
• Gleason>7 +/or Stage C/D – Follow-up studies in cohorts
• Comparable distributions for early/advanced
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Inclusion in CGEMS from PLCOof prostate cancer patients
1994
Oct 2001
Oct 2003
28 521 eligible participants
Aggressive Cancer0 0
737 624Non-aggressive Cancer
Matching with controls was performed for 737 aggressive cases and 493 randomly selected non-aggressive cases.
Non aggressive : stage <=2 (non invasive) and Gleason score <=6 Aggressive : stage >=3 (invasive) and Gleason score >=7
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Distribution of genotyped individuals usedfor the search of association
Prostate cancer status Number of times selected as controls at start of CGEMS project 0 1 2 3 Total
durin
g fo
llow
-up
Always negative 0 1 082 22 1 1 105 "controls"
Diagnosed with 461 26 1 0 488non-aggressive C. 1 177 casesDiagnosed with 673 16 0 0 689aggressive C.
Total 1 134 1 124 23 1 2 282
dropped : 1 XX DNA 4 unexpected dup 1 173
"controls" dropped : 1 XX DNA dropped :
2 unexpected dup 1 XX DNA 3 failed genotype 4 failed genotype
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Buccal Cell DNA and InfiniumTM II:ACS:CGEMS Pilot
23 matched blood and buccalArchived Buccal samples (2001/2002 in CPS-II)
Swish with ScopeTM and store after centrifugation
Extracted simultaneously with Autopure (Gentra)
Target 50ng/uL by QDNA (picogreen)4 outliers (0.5ng/uL- 35ng/uL)
HumanHap300 InfiniumTM II protocol Completion 99.02% Concordance 99.96%
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PLCO WGS QC Removal of Inconsistent Genotypes
Low Completion Rate (<95%) Duplicates: HapMap & PLCO qc samples
Fitness for HW Proportion in controls Exclusion Cut-off: <0.001
Re-Map SNP Positions Examine adjacent bps of SNPs Heterogeneity in Cases/Controls
Cryptic stratification STRUCTURE (Pritchard) Principal Component Analysis (Price Nat Gen 2006) Study Center (9 for PLCO)
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Discordance rate
Mean discordance
rate 2 10-4
Mean discordance
rate 2 10-4
28 individuals(with 24 duplicates)
Mean discordance
rate 1.4 10-3
PLCO CEPH-CGEMS CEPH-49 duplicate pairs 74 duplicate pairs HapMap
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log 1
0(p-
valu
e)
log-log quantile plot ofp-value for Hardy-Weinberg proportion
-2
-3
-4
-5
-6
-7 -2-3-4-5-6
20 simulations
Observed values
expected : 244 observed : 586
expected : 2600 observed : 3340
Exact test , 299 779 SNPs log10(quantile)
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QQ plot for ~300k SNPsQuantile
0
0.2
0.4
0.6
0.8
1.0
0 0.2 0.4 0.6 0.8 1.0p value
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Log1
0(pv
alue
)Log-Log quantile plot for p-value for the 4
statistical tests used307,256 SNPs
-3
-4
-5
Log10(quantile) -3-4-5
Sing. Sampl. No cov
Sing. Sampl. with cov
Incid. Den. Sampl. No cov
Incid. Den. Sampl with cov
-6
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Log(p-value)
Log(quantile)
Log/log quantile plot of p value (observed)
0
-2
-4
-6
-6 -4 -2 Log(quantile) 0
-1.9
-2.0
-2.1 -1.9-2.0-2.1
Log(p-value) or Log(quantile)
Log(quantile)
Log(p-value) Genomic control parameter = 0.99
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PLCO Recruitment SitesOpportunity to look at
geographic differences
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Admixture coefficient in PLCO samples
Asia Method : run merged PLCO data + HapMap data on STRUCTURE with 6000 SNPs having no pairwise r2 and high FST values. The population of origin of the HapMap samples is specified Result : Reliable identification of 3 outliers. They are all three control DNAs. and have to be removed from subsequent analysis
control
case
Africa Europe
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Log-Log quantile plot for p-values of 101 SNPs that differentiate the populations of South and North of Europe
0
-1
-2
Log10(quantile) 0-1-2
Sing. Sampl. No cov
Sing. Sampl. with cov
Incid. Den. Sampl. No cov
Incid. Den. Sampl with cov
Seldin et al. PLOS Genetics 2:1339-1351 (2006)
Log1
0(p-
valu
e)
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Lactase region Log10(p-value for association) LCT 0
rs2117511
rs6739713
rs1438307
rs6430585
rs9287442
rs1469996 rs4954633
rs2322659
rs2874874
rs3754690
rs3754689
rs309126
rs12478902
rs309160
136300k 136350k 136400k 136450k 136500k
-1
log10(0.05) rs4988235 rs182549
-2
-3
Bersaglieri et al. AJHG 74:1111-1120 (2004) position
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-2
-3Log 1
0Pva
lue
Log10Pvalue of the 4 d.f. χ2 test plotted against the position of the 8q24 SNP (rs#1447295)* in build 35
0
-1
-4
-5 126000000 127000000 128000000 129000000 130000000 131000000
mapinfoPosition in build35 *Amundadottir Nat Genet 2006
*Freedman PNAS 2006
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Characteristics of the SNPs demonstrating the strongest signal of association in 8q24
+-----------------------------------------------------------+| position Pval HW completion || rsnumber (b.35)
MAF controls rate
|-------------------------------------------------------|298. | rs4242382 128586755 .14 .7604 1 | 299. | rs7017300 128594450 .18 .1629 1 | 300. | rs7837688 128608542 .14 .8663 .999 | 301. | rs1447295 128554220 .14 .6012
1
| +------------------------------------------------------------+
Linkage disequilibrium (r2) with rs1447295 of the SNPs demonstrating the strongest signal of association
r2 with
| rs# position rs1447295 passoc | (b. 35)
| rs4242382 128586755 .94 .00007 || rs7017300 128594450 .71 .00009 || rs7837688 128608542 .84 .00003 || rs1447295 128554220 - .0003 |
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Prostate Scan8q24 Region
Genotype RR for Indolent Genotype RR for aggressive
rs number susceptibility
allele allele
frequency Heterozyg. Homozig. Heterozyg. Homozig.
rs1447295 A 0.1 1.08 1.45 1.24 1.46 rs4242382 A 0.1 1.13 1.39 1.27 1.39 rs7017300 C 0.13 1.14 1.63 1.17 1.37 rs7837688 T 0.1 1.14 1.36 1.26 1.54
Key Findings: 1. Comparable risk as original reports in Nat Genet and PNAS
2. Comparable risk for BPC3 (~6500 cases/controls)
3. Discovery of 1 and perhaps 2 additional loci
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Value-Added Analysis CGEMS Opportunity to investigate
• Gene:environment • Covariates: BMI, smoking, serum levels
• Multi-SNP Analysis • Gene:gene interactions
• Explore pathways • Follow-up in cohort studies in CGEMS
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http://cgems.cancer.gov
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CGEMS: caBIG PostingPre-Computed Analysis
Pre-computed Analysis No Restrictions
Raw Genotype Case/control Age (in 5 yrs) Family Hx (+/-)
Registration
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Association Finding
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Association Finding Report
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Population Frequency Report
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Acknowledgements
NCI Gilles Thomas Robert Hoover Joseph Fraumeni Daniela Gerhard Kevin Jacobs Zhaoming Wang Meredith Yeager Robert Welch Richard Hayes Sholom Wacholder Nilanjan Chatterjee Kai Yu Margaret Tucker Marianne Rivera-Silva
HSPH David Hunter Peter Kraft
ACS Heather Feigelson Carmen Rodriguez Eugene Calle Michael Thun