Limits...
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

Forest plot showing association between cancer risk and rs12970291 genotype in each data set.Legend is as for Fig. 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4664893&req=5

f3: Forest plot showing association between cancer risk and rs12970291 genotype in each data set.Legend is as for Fig. 1.

Mentions: There are SNPs that have previously been independently identified in GWAS of different phenotypes where the risk allele for one phenotype is the protective allele for another3940. In order to search for SNPs for which the same allele has differing directions of effect in CRC and EC, we conducted a fixed-effect meta-analysis with the odds ratios of all the CRC SNPs GWAS inverted (Supplementary Table 3). In this analysis, we discovered rs12970291 on chromosome 18q22, where the major G allele is protective in CRC (OR:0.78, 95%CI:0.69-0.90, 3.42 × 10−4) and confers risk in EC (OR:1.24, 95%CI: 1.11–1.38, p:1.11 × 10−4). In meta-analysis, the rs12970291 association reached genome-wide significance (OR:1.26, 95%CI:1.16–1.38, Pmeta:4.82 × 10−8; Fig. 3). Fine mapping analysis identified a large number of SNPs in high pairwise LD with rs12970291 (r2 > 0.85), in a 70 kb region that includes the gene TSHZ1, which is ~15 kb proximal to rs12970291 (Fig. 4). Seventeen SNPs had a stronger disease association than rs12970291 in fine mapping, with the lowest P value at rs35185115 (Pfine mapping = 1.08 × 10−6). Fine mapping of CRC and EC GWAS separately (Supplementary Figure 1) showed an association peak occurring in the same LD block between 10.5–51.8 kb downstream of TSHZ1, while an additional suggestive association signal near rs17263435 (PEC = 4.35 × 10−5) was not present in CRC (PCRC = 0.1). Several SNPs in the region have potential functional importance (Supplementary Table 4), and of particular note is the missense SNP rs3390274 (p.Ala468Thr) in the last exon of TSHZ1. SNPs with a pairwise LD of >0.4 with rs12970291 in the region were not significantly associated with mRNA level of TSHZ1 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)

Forest plot showing association between cancer risk and rs12970291 genotype in each data set.Legend is as for Fig. 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Forest plot showing association between cancer risk and rs12970291 genotype in each data set.Legend is as for Fig. 1.
Mentions: There are SNPs that have previously been independently identified in GWAS of different phenotypes where the risk allele for one phenotype is the protective allele for another3940. In order to search for SNPs for which the same allele has differing directions of effect in CRC and EC, we conducted a fixed-effect meta-analysis with the odds ratios of all the CRC SNPs GWAS inverted (Supplementary Table 3). In this analysis, we discovered rs12970291 on chromosome 18q22, where the major G allele is protective in CRC (OR:0.78, 95%CI:0.69-0.90, 3.42 × 10−4) and confers risk in EC (OR:1.24, 95%CI: 1.11–1.38, p:1.11 × 10−4). In meta-analysis, the rs12970291 association reached genome-wide significance (OR:1.26, 95%CI:1.16–1.38, Pmeta:4.82 × 10−8; Fig. 3). Fine mapping analysis identified a large number of SNPs in high pairwise LD with rs12970291 (r2 > 0.85), in a 70 kb region that includes the gene TSHZ1, which is ~15 kb proximal to rs12970291 (Fig. 4). Seventeen SNPs had a stronger disease association than rs12970291 in fine mapping, with the lowest P value at rs35185115 (Pfine mapping = 1.08 × 10−6). Fine mapping of CRC and EC GWAS separately (Supplementary Figure 1) showed an association peak occurring in the same LD block between 10.5–51.8 kb downstream of TSHZ1, while an additional suggestive association signal near rs17263435 (PEC = 4.35 × 10−5) was not present in CRC (PCRC = 0.1). Several SNPs in the region have potential functional importance (Supplementary Table 4), and of particular note is the missense SNP rs3390274 (p.Ala468Thr) in the last exon of TSHZ1. SNPs with a pairwise LD of >0.4 with rs12970291 in the region were not significantly associated with mRNA level of TSHZ1 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