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Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1.

Cheng TH, Thompson D, Painter J, O'Mara T, Gorman M, Martin L, Palles C, Jones A, Buchanan DD, Ko Win A, Hopper J, Jenkins M, Lindor NM, Newcomb PA, Gallinger S, Conti D, Schumacher F, Casey G, Giles GG, Pharoah P, Peto J, Cox A, Swerdlow A, Couch F, Cunningham JM, Goode EL, Winham SJ, Lambrechts D, Fasching P, Burwinkel B, Brenner H, Brauch H, Chang-Claude J, Salvesen HB, Kristensen V, Darabi H, Li J, Liu T, Lindblom A, Hall P, de Polanco ME, Sans M, Carracedo A, Castellvi-Bel S, Rojas-Martinez A, Aguiar Jnr S, Teixeira MR, Dunning AM, Dennis J, Otton G, Proietto T, Holliday E, Attia J, Ashton K, Scott RJ, McEvoy M, Dowdy SC, Fridley BL, Werner HM, Trovik J, Njolstad TS, Tham E, Mints M, Runnebaum I, Hillemanns P, Dörk T, Amant F, Schrauwen S, Hein A, Beckmann MW, Ekici A, Czene K, Meindl A, Bolla MK, Michailidou K, Tyrer JP, Wang Q, Ahmed S, Healey CS, Shah M, Annibali D, Depreeuw J, Al-Tassan NA, Harris R, Meyer BF, Whiffin N, Hosking FJ, Kinnersley B, Farrington SM, Timofeeva M, Tenesa A, Campbell H, Haile RW, Hodgson S, Carvajal-Carmona L, Cheadle JP, Easton D, Dunlop M, Houlston R, Spurdle A, Tomlinson I - Sci Rep (2015)

Bottom Line: A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03).Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk.Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

ABSTRACT
High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.

No MeSH data available.


Related in: MedlinePlus

Regional association plot for region around rs3184504.Plots are produced in LocusZoom and show the most strongly associated SNP, rs3184504 (purple diamond). rs7137828, intron of ATXN2, is the SNP with the second lowest P value. The primary aim of this analysis is to compare association signals among SNPs in the region. Therefore, the data are derived from a meta-analysis of genotyped or high-quality imputed SNPs in the GWAS data sets, and because imputation quality was more variable in iCOGS than in the GWAS data, the iCOGS samples are not included.
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f2: Regional association plot for region around rs3184504.Plots are produced in LocusZoom and show the most strongly associated SNP, rs3184504 (purple diamond). rs7137828, intron of ATXN2, is the SNP with the second lowest P value. The primary aim of this analysis is to compare association signals among SNPs in the region. Therefore, the data are derived from a meta-analysis of genotyped or high-quality imputed SNPs in the GWAS data sets, and because imputation quality was more variable in iCOGS than in the GWAS data, the iCOGS samples are not included.

Mentions: Meta-analysis of all CRC and EC data sets revealed a single genome-wide significant SNP, rs3184504, on chromosome 12q24 (OR: 1.10, 95% CI 1.07–1.13, Pmeta: 7.23 × 10−9, heterogeneity I2 = 0; Fig. 1, Supplementary Table 1). This SNP is a missense variant (p.Trp262Arg) in exon 4 of SH2B3. It has not previously been associated with either CRC or EC. The major [C] allele was consistently the risk allele in all datasets, including those analysed using the iCOGS array, on which the SNP was included due to promising, but unproven, associations below genome-wide significance in previous breast cancer and EC GWAS. An additional 3 SNPs (Fig. 2) in strong pairwise linkage disequilibrium (LD) with rs3184504 (r2 > 0.9) showed strong evidence of CRC-EC association (Pfine mapping < 10−5). These 4 SNPs lie in a 68kb region, that includes the genes SH2B3 and ATXN2, and their functional annotation is shown in Supplementary Table 2. None of the 4 SNPs was associated with the mRNA level of SH2B3, ATXN2 or other nearby genes in public eQTL databases (details not shown).


Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1.

Cheng TH, Thompson D, Painter J, O'Mara T, Gorman M, Martin L, Palles C, Jones A, Buchanan DD, Ko Win A, Hopper J, Jenkins M, Lindor NM, Newcomb PA, Gallinger S, Conti D, Schumacher F, Casey G, Giles GG, Pharoah P, Peto J, Cox A, Swerdlow A, Couch F, Cunningham JM, Goode EL, Winham SJ, Lambrechts D, Fasching P, Burwinkel B, Brenner H, Brauch H, Chang-Claude J, Salvesen HB, Kristensen V, Darabi H, Li J, Liu T, Lindblom A, Hall P, de Polanco ME, Sans M, Carracedo A, Castellvi-Bel S, Rojas-Martinez A, Aguiar Jnr S, Teixeira MR, Dunning AM, Dennis J, Otton G, Proietto T, Holliday E, Attia J, Ashton K, Scott RJ, McEvoy M, Dowdy SC, Fridley BL, Werner HM, Trovik J, Njolstad TS, Tham E, Mints M, Runnebaum I, Hillemanns P, Dörk T, Amant F, Schrauwen S, Hein A, Beckmann MW, Ekici A, Czene K, Meindl A, Bolla MK, Michailidou K, Tyrer JP, Wang Q, Ahmed S, Healey CS, Shah M, Annibali D, Depreeuw J, Al-Tassan NA, Harris R, Meyer BF, Whiffin N, Hosking FJ, Kinnersley B, Farrington SM, Timofeeva M, Tenesa A, Campbell H, Haile RW, Hodgson S, Carvajal-Carmona L, Cheadle JP, Easton D, Dunlop M, Houlston R, Spurdle A, Tomlinson I - Sci Rep (2015)

Regional association plot for region around rs3184504.Plots are produced in LocusZoom and show the most strongly associated SNP, rs3184504 (purple diamond). rs7137828, intron of ATXN2, is the SNP with the second lowest P value. The primary aim of this analysis is to compare association signals among SNPs in the region. Therefore, the data are derived from a meta-analysis of genotyped or high-quality imputed SNPs in the GWAS data sets, and because imputation quality was more variable in iCOGS than in the GWAS data, the iCOGS samples are not included.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664893&req=5

f2: Regional association plot for region around rs3184504.Plots are produced in LocusZoom and show the most strongly associated SNP, rs3184504 (purple diamond). rs7137828, intron of ATXN2, is the SNP with the second lowest P value. The primary aim of this analysis is to compare association signals among SNPs in the region. Therefore, the data are derived from a meta-analysis of genotyped or high-quality imputed SNPs in the GWAS data sets, and because imputation quality was more variable in iCOGS than in the GWAS data, the iCOGS samples are not included.
Mentions: Meta-analysis of all CRC and EC data sets revealed a single genome-wide significant SNP, rs3184504, on chromosome 12q24 (OR: 1.10, 95% CI 1.07–1.13, Pmeta: 7.23 × 10−9, heterogeneity I2 = 0; Fig. 1, Supplementary Table 1). This SNP is a missense variant (p.Trp262Arg) in exon 4 of SH2B3. It has not previously been associated with either CRC or EC. The major [C] allele was consistently the risk allele in all datasets, including those analysed using the iCOGS array, on which the SNP was included due to promising, but unproven, associations below genome-wide significance in previous breast cancer and EC GWAS. An additional 3 SNPs (Fig. 2) in strong pairwise linkage disequilibrium (LD) with rs3184504 (r2 > 0.9) showed strong evidence of CRC-EC association (Pfine mapping < 10−5). These 4 SNPs lie in a 68kb region, that includes the genes SH2B3 and ATXN2, and their functional annotation is shown in Supplementary Table 2. None of the 4 SNPs was associated with the mRNA level of SH2B3, ATXN2 or other nearby genes in public eQTL databases (details not shown).

Bottom Line: A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03).Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk.Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

ABSTRACT
High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.

No MeSH data available.


Related in: MedlinePlus