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

Genetic Genetic susceptibility: susceptibility:

Polymorphisms of Polymorphisms of the 8q24 the 8q24

chromosome chromosome S. Lani ParkS. Lani Park

05/07/0905/07/09

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.

Amundadottir LT, Nature Genetics, 2006

Amundadottir, LT, Nature Genetics, 2006

Yeager M, nature genetics, May 2007

Haiman CA, Nature Genetics, May 2007

Haiman CA, Nature Genetics, May 2007

Haiman CA, Nature Genetics, August 2007

8q24 and Breast Cancer8q24 and Breast Cancer

Garcia-Closas M, Plos Genetics, April 2008

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

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

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.

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.

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)

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

LA

Lung

UADT (squam)

Oroph.

Larynx

Naso.

Associations between 8q24 SNPs and smoking related cancers

Taixing

Esoph.

Stomach

Liver

MSKCC Bladder

Associations between 8q24 SNPs and smoking related cancers

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

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.

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

Associations between rs6983267rs6983267 and cancer sites. Wokolorczyk D, Cancer Research, Dec 2008

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.