Genetic Susceptibility to p y Endometrial Cancer: an update d Immaculata De Vivo Harvard Medical School Harvard School of Public Health Brigham and Women’s Hospital March 17 th , 2014 March 17 , 2014
Outline Outline • Part 1: GWAS • Part 2: EXWAS • Part 3: Future Part 3: Future
Part 1: GWAS Part 1: GWAS
Epidemiology of Endometrial Cancer Consortium (E2C2) ( ) WTCCC AHS NHS PECS FHCRC WISE CONN Turin PLCO CTS EDGE EDGE SECGS MEC MEC ACS ANECS/ SEARCH SEARCH
Discovery – Main Results Discovery Main Results N = 5,472 5
Epidemiology of Endometrial Cancer Consortium (E2C2) ( ) WTCCC AHS NHS PECS FHCRC WISE CONN Turin PLCO CTS EDGE EDGE SECGS MEC MEC ACS ANECS/ SEARCH SEARCH
Fast track replication * (participants of European non-Hispanic ancestry**, N=4238) GWAS Replication GWAS + Replication SNP CHR A Beta StdErr Q P-Assoc P-Het Beta StdErr Q P-Assoc P-Het Beta StdErr Q P-Assoc P-Het RS10739046 9p24.2 C -0.1949 0.0416 2.10 2.8E-06 0.91 -0.0119 0.0475 3.48 0.80 0.48 -0.1155 0.0313 11.88 2.2E-04 0.04 RS10822320 10q21.3 T -0.2849 0.0641 5.67 8.9E-06 0.34 0.0965 0.0717 1.82 0.18 0.61 -0.1154 0.0478 17.54 1.6E-02 0.004 RS11651755 (HNF1B) 17q12 C -0.0684 0.0434 5.98 1.2E-01 0.31 -0.1497 0.0442 3.61 0.0007 0.46 -0.1083 0.0310 5.33 4.1E-01 0.38 RS1352075 11q13.3 C -0.2011 0.0442 2.29 5.3E-06 0.81 -0.0671 0.0517 3.41 0.19 0.33 -0.1445 0.0336 7.30 1.7E-05 0.20 RS4430796 (HNF1B) 17q12 G -0.0845 0.0399 9.02 3.4E-02 0.17 -0.1249 0.0440 3.86 0.005 0.42 -0.1027 0.0296 4.33 5.2E-04 0.50 RS4697273 RS4697273 4p15 2 4p15.2 A A -0 2487 0.2487 0.0534 0 0534 5.47 3.2E 06 5 47 3 2E-06 0 36 0.36 0.0515 0 0515 0.0539 0 0539 1.06 1 06 0 34 0.34 0 90 0.90 -0 1001 0.1001 0.0379 0 0379 16 71 16.71 8.3E 03 8 3E-03 0 005 0.005 RS9344 11q13.3 A 0.1840 0.0397 2.66 3.6E-06 0.85 0.0542 0.0514 2.20 0.29 0.53 0.1354 0.0314 6.19 1.6E-05 0.29 RS9369262 6p24.1 C -0.4497 0.0986 0.00 5.1E-06 1.00 -0.0465 0.0468 0.99 0.32 0.91 -0.1207 0.0423 14.64 4.3E-03 0.01 RS941990 6p22.3 G 0.2090 0.0469 3.69 8.3E-06 0.72 0.0126 0.0600 5.82 0.83 0.12 0.1346 0.0369 12.47 2.7E-04 0.03 Note: Highlighted SNPs corresponds to the published hits by Spurdle et al 2011 Note: Highlighted SNPs corresponds to the published hits by Spurdle et al. 2011 * by taqman ** Contributing studies: AHS, EDGE, FHCRC, MEC, CPSII, Turin, Wise
Conclusions from the GWAS Conclusions from the GWAS • No novel common variants were associated No novel common variants were associated with EC risk • HNF1B locus was replicated • Limitations: – Sample size – Tumor heterogeneity Tumor heterogeneity
Part 2: EXWAS Part 2: EXWAS Chen M, Crous-Bou M, Setiawan VM, Prescott J, Olson SH, Wemtzensen N, Black A Brinton L Chen C Chen C Cook LS Doherty J Friedenreich CM Hankinson SE Hartge A, Brinton L, Chen C, Chen C, Cook LS, Doherty J, Friedenreich CM, Hankinson SE, Hartge P, Henderson BE, Hunter DJ, Le Marchand L, Liang X, Lissowska J, Lu L, Orlow I, Petruzella S, Polidoro S, Pooler P, Rebbeck TR, Risch H, Sacerdote C, Schumacher F, Sheng X, Shu X, Weiss NS, Xia L, Van Den Berg D, Yang HP, Yu H, Chanock S, Haiman C, Kraft P, De Vivo I. Exome-Wide Association Study of Endometrial Cancer in a Multiethnic Population. Under Review in PLoS One since February 2014.
Exome Genotyping Arrays Exome Genotyping Arrays Exome : parts of the genome that encode proteins • Genotyping costs < sequencing costs – Permits larger sample sizes • Focus: Protein altering variants – Non-synonymous (260,054 candidates) – Splicing (12,662 candidates) Splicing (12,662 candidates) – Stop altering (7,137 candidates) • Additional variation – GWAS hits, ancestry informative markers, random GWAS hits ancestry informative markers random synonymous variants, etc. • Custom content – 2000 SNPs from E2C2 GWAS discovery phase 2000 SNPs from E2C2 GWAS discovery phase
Epidemiology of Endometrial Cancer Consortium (E2C2) ( ) WTCCC AHS NHS PECS FHCRC WISE CONN Turin PLCO CTS EDGE EDGE SECGS MEC MEC ACS ANECS/ SEARCH SEARCH
MAF within reported ethnicities MAF within reported ethnicities
Single Variant Association Analysis (all Ethnicities) N = 2,833 ,
Single Variant Association Analysis (only Caucasian) N = 1,681 ,
Single Variant Association Analysis Single Variant Association Analysis Variant Gene/Locus / MAF OR P-value P-value (all ethnicities) (only Caucasians) rs1953358 LINC00520 0.49 1.36 (1.20, 1.53) 4.76E-07 3.35E-06 rs8178648 PROS1 0.09 1.71 (1.37, 2.12) ( , ) 1.53E-06 3.00E-05 rs9399840 n/a 0.47 0.75 (0.67, 0.85) 3.01E-06 5.18E-05 exm1401784 ATP8B3 0.23 0.72 (0.61, 0.83) 1.92E-05 6.49E-05 rs6926980 rs6926980 KIAA1586 KIAA1586 0 23 0.23 0 75 (0 65 0 87) 0.75 (0.65, 0.87) 7 95E 05 7.95E-05 6 56E 05 6.56E-05
Conclusions from the EXWAS Conclusions from the EXWAS • No rare variants reach significance with risk of EC No rare variants reach significance with risk of EC • Limitations: – small sample size – predominantly designed for those with European ancestry – incomplete coverage of all functional variants in exome • Strengths: • Strengths: – first exome chip analysis of endometrial cancer – comprehensive study of a multi-ethnic population comprehensive study of a multi ethnic population
Part 3: Future Part 3: Future • Meta-analysis Meta analysis • Gene-environment-wide interaction studies G i id i i di (GEWIS) • Genetic susceptibility by subtype p y y yp
Th Thanks! k !
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