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

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Presentation on theme: "Genetic susceptibility: Polymorphisms of the 8q24 chromosome S. Lani Park 05/07/09."— Presentation transcript:

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

6

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8 Yeager M, nature genetics, May 2007

9 Haiman CA, Nature Genetics, May 2007

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11 Haiman CA, Nature Genetics, August 2007

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

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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 – rs association dependent on ER+ status Breast – rs association dependent on ER+ status Colon – rs Colon – rs Endometrial and testes (null association) Endometrial and testes (null association) Bladder – rs Bladder – rs 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: rs Region 1: rs Mb Mb Region 2: rs Region 2: rs Mb Mb Region 3: rs Region 3: rs Mb 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 (%) Total Age range – Age, mean 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 ≥ q24 region contains 780 common SNPs, 454 which have MAF ≥ 0.05 Preliminary bioinformatics analyses identified rs an excellent SNP for functional assessment. Preliminary bioinformatics analyses identified rs 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 , 3 SNPs lie within potentially interesting regions, strong evidence for nominating one as the strongest candidate is still lacking. Telomeric region of , 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: Mb rs Region 2: Mb Region 3: Mb rs Region 4: Mb Region 5: Mb rs Ghoussaini M, JNCI, July 2008

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

26 Conclusions: Prior studies and our findings support the hypothesis that 8q24 SNPs particularly rs , 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 rs , 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.


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