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Genetic susceptibility: Polymorphisms of the 8q24 chromosome

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

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Genetic susceptibility: Polymorphisms of the 8q24 chromosome

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  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.

  3. Amundadottir LT, Nature Genetics, 2006

  4. Amundadottir, LT, Nature Genetics, 2006

  5. Yeager M, nature genetics, May 2007

  6. Haiman CA, Nature Genetics, May 2007

  7. Haiman CA, Nature Genetics, May 2007

  8. Haiman CA, Nature Genetics, August 2007

  9. 8q24 and Breast Cancer Garcia-Closas M, Plos Genetics, April 2008

  10. 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

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

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

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

  14. Baseline characteristics of each study

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

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

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

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

  19. Findings from resequencing analysis of 136 kb region of 8q24 chromosome (Yeager M, Hum Genetics, August 2008) • Platform Roche/454 sequencing technology. • 8q24 region contains 780 common SNPs, 454 which have MAF ≥ 0.05 • 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 • Telomeric region of 1447295, 3 SNPs lie within potentially interesting regions, strong evidence for nominating one as the strongest candidate is still lacking.

  20. 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

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

  22. 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). • 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. • 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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