genetic susceptibility: polymorphisms of the 8q24 chromosome s. lani park 05/07/09
TRANSCRIPT
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Genetic Genetic susceptibility: susceptibility:
Polymorphisms of Polymorphisms of the 8q24 the 8q24
chromosome chromosome S. Lani ParkS. Lani Park
05/07/0905/07/09
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BackgroundBackground In 2006 and 2007 GWAS studies identified In 2006 and 2007 GWAS studies identified
associations between SNPs in the 8q24 region associations between SNPs in the 8q24 region and prostate cancer among Icelandic, Swedish, and prostate cancer among Icelandic, Swedish, European American, African American, and European American, African American, and the Multiethnic Cohort populations. the Multiethnic Cohort populations.
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Amundadottir LT, Nature Genetics, 2006
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Amundadottir, LT, Nature Genetics, 2006
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Yeager M, nature genetics, May 2007
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Haiman CA, Nature Genetics, May 2007
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Haiman CA, Nature Genetics, May 2007
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Haiman CA, Nature Genetics, August 2007
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8q24 and Breast Cancer8q24 and Breast Cancer
Garcia-Closas M, Plos Genetics, April 2008
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Study Aim:Study Aim:
We hypothesize SNPs in the 8q24 We hypothesize SNPs in the 8q24 region may be associated with region may be associated with tobacco smoking related cancer tobacco smoking related cancer sites: lung, oropharynx, larynx, sites: lung, oropharynx, larynx, esophagus, stomach, liver, bladder, esophagus, stomach, liver, bladder, nasopharynx, and kidneynasopharynx, and kidney
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Study JustificationStudy Justification GWAS prostate findingsGWAS prostate findings Studies have investigated the association Studies have investigated the association
between these SNPs in the following cancer between these SNPs in the following cancer sites:sites: Breast – rs13281615 association dependent on Breast – rs13281615 association dependent on
ER+ statusER+ status Colon – rs6983267 Colon – rs6983267 Endometrial and testes (null association)Endometrial and testes (null association) Bladder – rs9642880Bladder – 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 cancersRegion has been amplified within many cancers Lies between FAM84B, POU5F1P1, and MYCLies between FAM84B, POU5F1P1, and MYC
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Neighboring 8q24 genesNeighboring 8q24 genes
POU5F1P1POU5F1P1 Pseudo gene, physiological role unknown. Pseudo gene, physiological role unknown. Expression of this transcript in cancer tissues.Expression of this transcript in cancer tissues.
MYCMYC Protooncogene encodes a DNA-binding factor Protooncogene encodes a DNA-binding factor
that can activate and repress transcription that can activate and repress transcription Amplification of this region found in many Amplification of this region found in many
cancer sitescancer sites FAM84BFAM84B
Little known about function, other than Little known about function, other than describes as breast cancer membrane describes as breast cancer membrane associated protein.associated protein.
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Study DesignStudy Design Selected the strongest single Selected the strongest single
association in three 8q24 “regions:”association in three 8q24 “regions:” Region 1: rs1447295Region 1: rs1447295
128.54 -128.64 Mb128.54 -128.64 Mb Region 2: rs16901979Region 2: rs16901979
128.14 -128.54 Mb128.14 -128.54 Mb Region 3: rs6983267Region 3: rs6983267
128.47 -128.54 Mb128.47 -128.54 Mb Used data from 3 case control Used data from 3 case control
studies: Los Angeles County Study, studies: Los Angeles County Study, MSKCC Study, and China Taixing MSKCC Study, and China Taixing City Study.City Study.
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Baseline characteristics of Baseline characteristics of each studyeach study
LA Study Taixing City Study MSKCC study
Lung Cancer Cases (%)
UADT cancer Cases (%)
Controls (%)
Stomach Cancer Cases (%)
Esophageal Cancer Cases (%)
Liver Cancer Cases (%)
Controls (%)
Bladder Cancer Cases (%)
Controls (%)
Total 611 601 1040 206 218 204 415 233 204
Age range 32-59 20-59 17-65 30-82 30 – 84 22-83 21-84 32-84 17-80
Age, mean 52.2 50.3 49.9 61.5 60.6 53.8 57.7 64.8 42.0
Gender
Males 303 (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)
Females
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) 0 (0.0) 10 (2.4) 138 (59.2) 170 (83.3)
Smoking
Never 110 (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)
Ever 501 (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)
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LA White MSKCC White LA Afr-Am LA Mexican LA Asian Taixing
SNP N (%) N (%) N (%) N (%) N (%) N (%) rs1447295
CC 457 (79) 140 (89) 42 (53) 113 (81) 30 (59) 276 (71) CA 113 (20) 17 (11) 30 (38) 25 (18) 19 (37) 101 (26) AA 7 (1) 0 7 (9) 1 (1) 2 (4) 11 (3) C 1027 (89) 281 (95) 114 (72) 251 (90) 79 (78) 653 (84) A 127 (11) 17 (5) 44 (28) 27 (10) 23 (23) 43 (16) HWE P-value 0.996 0.473 0.625 0.763 0.634 0.634
rs16901979 CC 531 (92) 149 (94) 23 (29) 128 (93) 33 (65) 207 (55) CA 44 (8) 9 (6) 48 (61) 9 (7) 13 (26) 143 (38) AA 2 (0.4) 0 8 (10) 1 (7) 5 (10) 30 (8) C 1106 (96) 307 (97) 94 (60) 265 (96) 79 (78) 557 (73) A 48 (4) 9 (3) 64 (41) 11 (4) 23 (23) 203 (27) HWE P-value 0.30 0.713 0.021 0.082 0.053 0.449
rs6983267 TT 138 (24) 34 (22) 1 (1) 27 (20) 17 (33) 146 (38) TG 287 (50) 73 (47) 23 (29) 61 (44) 28 (54) 165 (43) GG 150 (26) 50 (32) 55 (70) 50 (36) 7 (14) 74 (19) T 563 (49) 141 (45) 24 (16) 115 (42) 62 (60) 457 (59) G 587 (51) 173 (55) 133 (84) 161 (58) 42 (40) 313 (41) HWE P-value 0.975 0.450 0.409 0.287 0.394 0.028
Genotype and Allele frequencies of Genotype and Allele frequencies of 8q24 variants, stratified by Ethnicity 8q24 variants, stratified by Ethnicity
and Study and Study
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LA
Lung
UADT (squam)
Oroph.
Larynx
Naso.
Associations between 8q24 SNPs and smoking related cancers
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Taixing
Esoph.
Stomach
Liver
MSKCC Bladder
Associations between 8q24 SNPs and smoking related cancers
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Association between 8q24 and 7 Association between 8q24 and 7 smoking related cancer sites, smoking related cancer sites, stratified by smoking statusstratified by smoking status
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Findings from resequencing analysis Findings from resequencing analysis of 136 kb region of 8q24 chromosome of 136 kb region of 8q24 chromosome
(Yeager M, Hum Genetics, August 2008)(Yeager M, Hum Genetics, August 2008)
Platform Roche/454 sequencing technology.Platform Roche/454 sequencing technology. 8q24 region contains 780 common SNPs, 454 8q24 region contains 780 common SNPs, 454
which have MAF ≥ 0.05which have MAF ≥ 0.05 Preliminary bioinformatics analyses Preliminary bioinformatics analyses
identified rs6983267 an excellent SNP for identified rs6983267 an excellent SNP for functional assessment. functional assessment. Lies in a region that is both highly conserved Lies in a region that is both highly conserved
across vertebrates predicted to likely contain across vertebrates predicted to likely contain regulatory potential and enhancer-elementregulatory potential and enhancer-element
Telomeric region of 1447295, 3 SNPs lie Telomeric region of 1447295, 3 SNPs lie within potentially interesting regions, strong within potentially interesting regions, strong evidence for nominating one as the strongest evidence for nominating one as the strongest candidate is still lacking.candidate is still lacking.
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Genotyped and found 5 different Genotyped and found 5 different haplotype blockshaplotype blocks
Region 1: 128.14-128.28 Mb Region 1: 128.14-128.28 Mb rs16901979 rs16901979
Region 2: 128.35-128.51 Mb Region 2: 128.35-128.51 Mb Region 3: 128.47-128.50 MbRegion 3: 128.47-128.50 Mb
rs6983267rs6983267 Region 4: 128.50-128.54 MbRegion 4: 128.50-128.54 Mb Region 5: 128.54-128.62 MbRegion 5: 128.54-128.62 Mb
rs1447295rs1447295
Ghoussaini M, JNCI, July 2008
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Associations between rs6983267rs6983267 and cancer sites. Wokolorczyk D, Cancer Research, Dec 2008
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Conclusions:Conclusions: Prior studies and our findings support the Prior studies and our findings support the
hypothesis that 8q24 SNPs particularly rs6983267, hypothesis that 8q24 SNPs particularly rs6983267, plays a role in cancer development (prostate, colon, plays a role in cancer development (prostate, colon, breast, bladder, UADT, liver, and thyroid).breast, bladder, UADT, liver, and thyroid).
This role may be through a a tobacco-related This role may be through a a tobacco-related carcinogenic pathway or a combination of different carcinogenic pathway or a combination of different carcinogenic pathways. carcinogenic pathways.
When investigating genetic susceptibility genes in When investigating genetic susceptibility genes in cancer one should consider the major risk factors of cancer one should consider the major risk factors of the cancer site. the cancer site.
Laboratory-based functional studies and large Laboratory-based functional studies and large epidemiologic studies in multiple populations should epidemiologic studies in multiple populations should be conducted to further understand the role of 8q24 be conducted to further understand the role of 8q24 in cancer.in cancer.