1. Genetic susceptibility: Polymorphisms of the 8q24 chromosome S. Lani Park 05/07/09

2. Background In 2006 and 2007 GWAS studies identified associations between SNPs in the 8q24 region and prostate cancer among Icelandic, Swedish, European American, African American, and the Multiethnic Cohort populations. In 2006 and 2007 GWAS studies identified associations between SNPs in the 8q24 region and prostate cancer among Icelandic, Swedish, European American, African American, and the Multiethnic Cohort populations.

3. Kingsmore, 2008

4. Amundadottir LT, Nature Genetics, 2006

5. Amundadottir, LT, Nature Genetics, 2006

8. Yeager M, nature genetics, May 2007

9. Haiman CA, Nature Genetics, May 2007

11. Haiman CA, Nature Genetics, August 2007

12. 8q24 and Breast Cancer Garcia-Closas M, Plos Genetics, April 2008

14. Study Aim: We hypothesize SNPs in the 8q24 region may be associated with tobacco smoking related cancer sites: lung, oropharynx, larynx, esophagus, stomach, liver, bladder, nasopharynx, and kidney We hypothesize SNPs in the 8q24 region may be associated with tobacco smoking related cancer sites: lung, oropharynx, larynx, esophagus, stomach, liver, bladder, nasopharynx, and kidney

15. Study Justification GWAS prostate findings GWAS prostate findings Studies have investigated the association between these SNPs in the following cancer sites: Studies have investigated the association between these SNPs in the following cancer sites: Breast – rs13281615 association dependent on ER+ status Breast – rs13281615 association dependent on ER+ status Colon – rs6983267 Colon – rs6983267 Endometrial and testes (null association) Endometrial and testes (null association) Bladder – rs9642880 Bladder – rs9642880 GWAS OR=1.19 (1.12, 1.27) GWAS OR=1.19 (1.12, 1.27) Chinese population OR=1.43 (1.18, 1.75) Chinese population OR=1.43 (1.18, 1.75) 8q24 and cancer: 8q24 and cancer: Region has been amplified within many cancers Region has been amplified within many cancers Lies between FAM84B, POU5F1P1, and MYC Lies between FAM84B, POU5F1P1, and MYC

16. Neighboring 8q24 genes POU5F1P1 POU5F1P1 Pseudo gene, physiological role unknown. Pseudo gene, physiological role unknown. Expression of this transcript in cancer tissues. Expression of this transcript in cancer tissues. MYC MYC Protooncogene encodes a DNA-binding factor that can activate and repress transcription Protooncogene encodes a DNA-binding factor that can activate and repress transcription Amplification of this region found in many cancer sites Amplification of this region found in many cancer sites FAM84B FAM84B Little known about function, other than describes as breast cancer membrane associated protein. Little known about function, other than describes as breast cancer membrane associated protein.

17. Study Design Selected the strongest single association in three 8q24 “regions:” Selected the strongest single association in three 8q24 “regions:” Region 1: rs1447295 Region 1: rs1447295 128.54 -128.64 Mb 128.54 -128.64 Mb Region 2: rs16901979 Region 2: rs16901979 128.14 -128.54 Mb 128.14 -128.54 Mb Region 3: rs6983267 Region 3: rs6983267 128.47 -128.54 Mb 128.47 -128.54 Mb Used data from 3 case control studies: Los Angeles County Study, MSKCC Study, and China Taixing City Study. Used data from 3 case control studies: Los Angeles County Study, MSKCC Study, and China Taixing City Study.

18. Baseline characteristics of each study LA StudyTaixing City StudyMSKCC study Lung Cancer Cases (%) UADT cancer Cases (%) Controls (%) Stomach Cancer Cases (%) Esophage al Cancer Cases (%) Liver Cancer Cases (%) Controls (%) Bladder Cancer Cases (%) Controls (%) Total6116011040206218204415233204 Age range32-5920-5917-6530-8230 – 8422-8321-8432-8417-80 Age, mean52.250.349.961.560.653.857.764.842.0 Gender Males303 (49.6)391 (74.2)623 (59.9)138 (67.0)141 (64.7)159 (77.9)287 (69.2)206 (83.4)156 (77.2) Female s 308 (50.4)136 (25.8)417 (40.1)68 (33.0)77 (35.3)45 (22.1)128 (30.8)41 (16.6)46 (22.8) Education < High school 265 (43.4)240 (45.5)300 (28.9)204 (99.5)215 (100.0) 204 (100.0) 405 (97.6)95 (40.8)34 (16.7) >High School 346 (56.6)287 (54.5)739 (71.1)1 (0.5)0 (0.0) 10 (2.4)138 (59.2)170 (83.3) Smoking Never110 (18.0)164 (31.1)491 (47.3)92 (45.8)94 (43.1)85 (44.3)217 (52.4)42 (17.3)92 (46.0) Ever501 (82.0)363 (68.9)548 (52.7)109 (54.2)117 (53.7)107 (55.7)197 (47.9)201 (82.7)108 (54)

19. Genotype and Allele frequencies of 8q24 variants, stratified by Ethnicity and Study

20. LA Lung UADT (squam) Oroph. Larynx Naso. Associations between 8q24 SNPs and smoking related cancers

21. Taixing Esoph. Stomach Liver MSKCC Bladder Associations between 8q24 SNPs and smoking related cancers

22. Association between 8q24 and 7 smoking related cancer sites, stratified by smoking status

23. Findings from resequencing analysis of 136 kb region of 8q24 chromosome (Yeager M, Hum Genetics, August 2008) Platform Roche/454 sequencing technology. Platform Roche/454 sequencing technology. 8q24 region contains 780 common SNPs, 454 which have MAF ≥ 0.05 8q24 region contains 780 common SNPs, 454 which have MAF ≥ 0.05 Preliminary bioinformatics analyses identified rs6983267 an excellent SNP for functional assessment. Preliminary bioinformatics analyses identified rs6983267 an excellent SNP for functional assessment. Lies in a region that is both highly conserved across vertebrates predicted to likely contain regulatory potential and enhancer-element Lies in a region that is both highly conserved across vertebrates predicted to likely contain regulatory potential and enhancer-element Telomeric region of 1447295, 3 SNPs lie within potentially interesting regions, strong evidence for nominating one as the strongest candidate is still lacking. Telomeric region of 1447295, 3 SNPs lie within potentially interesting regions, strong evidence for nominating one as the strongest candidate is still lacking.

24. Genotyped and found 5 different haplotype blocks Region 1: 128.14-128.28 Mb rs16901979 Region 2: 128.35-128.51 Mb Region 3: 128.47-128.50 Mb rs6983267 Region 4: 128.50-128.54 Mb Region 5: 128.54-128.62 Mb rs1447295 Ghoussaini M, JNCI, July 2008

25. rs6983267 Associations between rs6983267 and cancer sites. Wokolorczyk D, Cancer Research, Dec 2008

26. Conclusions: Prior studies and our findings support the hypothesis that 8q24 SNPs particularly rs6983267, plays a role in cancer development (prostate, colon, breast, bladder, UADT, liver, and thyroid). Prior studies and our findings support the hypothesis that 8q24 SNPs particularly rs6983267, plays a role in cancer development (prostate, colon, breast, bladder, UADT, liver, and thyroid). This role may be through a a tobacco-related carcinogenic pathway or a combination of different carcinogenic pathways. This role may be through a a tobacco-related carcinogenic pathway or a combination of different carcinogenic pathways. When investigating genetic susceptibility genes in cancer one should consider the major risk factors of the cancer site. When investigating genetic susceptibility genes in cancer one should consider the major risk factors of the cancer site. Laboratory-based functional studies and large epidemiologic studies in multiple populations should be conducted to further understand the role of 8q24 in cancer. Laboratory-based functional studies and large epidemiologic studies in multiple populations should be conducted to further understand the role of 8q24 in cancer.