Browsing by Author "Drew DA"

Now showing 1 - 5 of 5
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    Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk
    (Springer Nature Limited, 2024-04-01) Tian Y; Lin Y; Qu C; Arndt V; Baurley JW; Berndt SI; Bien SA; Bishop DT; Brenner H; Buchanan DD; Budiarto A; Campbell PT; Carreras-Torres R; Casey G; Chan AT; Chen R; Chen X; Conti DV; Díez-Obrero V; Dimou N; Drew DA; Figueiredo JC; Gallinger S; Giles GG; Gruber SB; Gunter MJ; Harlid S; Harrison TA; Hidaka A; Hoffmeister M; Huyghe JR; Jenkins MA; Jordahl KM; Joshi AD; Keku TO; Kawaguchi E; Kim AE; Kundaje A; Larsson SC; Marchand LL; Lewinger JP; Li L; Moreno V; Morrison J; Murphy N; Nan H; Nassir R; Newcomb PA; Obón-Santacana M; Ogino S; Ose J; Pardamean B; Pellatt AJ; Peoples AR; Platz EA; Potter JD; Prentice RL; Rennert G; Ruiz-Narvaez EA; Sakoda LC; Schoen RE; Shcherbina A; Stern MC; Su Y-R; Thibodeau SN; Thomas DC; Tsilidis KK; van Duijnhoven FJB; Van Guelpen B; Visvanathan K; White E; Wolk A; Woods MO; Wu AH; Peters U; Gauderman WJ; Hsu L; Chang-Claude J
    BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
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    Genome-wide interaction analysis of folate for colorectal cancer risk.
    (Elsevier B.V., 2023-11) Bouras E; Kim AE; Lin Y; Morrison J; Du M; Albanes D; Barry EL; Baurley JW; Berndt SI; Bien SA; Bishop TD; Brenner H; Budiarto A; Burnett-Hartman A; Campbell PT; Carreras-Torres R; Casey G; Cenggoro TW; Chan AT; Chang-Claude J; Conti DV; Cotterchio M; Devall M; Diez-Obrero V; Dimou N; Drew DA; Figueiredo JC; Giles GG; Gruber SB; Gunter MJ; Harrison TA; Hidaka A; Hoffmeister M; Huyghe JR; Joshi AD; Kawaguchi ES; Keku TO; Kundaje A; Le Marchand L; Lewinger JP; Li L; Lynch BM; Mahesworo B; Männistö S; Moreno V; Murphy N; Newcomb PA; Obón-Santacana M; Ose J; Palmer JR; Papadimitriou N; Pardamean B; Pellatt AJ; Peoples AR; Platz EA; Potter JD; Qi L; Qu C; Rennert G; Ruiz-Narvaez E; Sakoda LC; Schmit SL; Shcherbina A; Stern MC; Su Y-R; Tangen CM; Thomas DC; Tian Y; Um CY; van Duijnhoven FJ; Van Guelpen B; Visvanathan K; Wang J; White E; Wolk A; Woods MO; Ulrich CM; Hsu L; Gauderman WJ; Peters U; Tsilidis KK
    Background Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate’s role in CRC. Objectives Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. Methods We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). Results Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. Conclusions Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.
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    Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures
    (Springer Nature Limited, 6/06/2022) Georgeson P; Harrison TA; Pope BJ; Zaidi SH; Qu C; Steinfelder RS; Lin Y; Joo JE; Mahmood K; Clendenning M; Walker R; Amitay EL; Berndt SI; Brenner H; Campbell PT; Cao Y; Chan AT; Chang-Claude J; Doheny KF; Drew DA; Figueiredo JC; French AJ; Gallinger S; Giannakis M; Giles GG; Gsur A; Gunter MJ; Hoffmeister M; Hsu L; Huang W-Y; Limburg P; Manson JE; Moreno V; Nassir R; Nowak JA; Obón-Santacana M; Ogino S; Phipps AI; Potter JD; Schoen RE; Sun W; Toland AE; Trinh QM; Ugai T; Macrae FA; Rosty C; Hudson TJ; Jenkins MA; Thibodeau SN; Winship IM; Peters U; Buchanan DD
    Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.
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    Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses.
    (Springer Nature, 2023-06-26) Dimou N; Kim AE; Flanagan O; Murphy N; Diez-Obrero V; Shcherbina A; Aglago EK; Bouras E; Campbell PT; Casey G; Gallinger S; Gruber SB; Jenkins MA; Lin Y; Moreno V; Ruiz-Narvaez E; Stern MC; Tian Y; Tsilidis KK; Arndt V; Barry EL; Baurley JW; Berndt SI; Bézieau S; Bien SA; Bishop DT; Brenner H; Budiarto A; Carreras-Torres R; Cenggoro TW; Chan AT; Chang-Claude J; Chanock SJ; Chen X; Conti DV; Dampier CH; Devall M; Drew DA; Figueiredo JC; Giles GG; Gsur A; Harrison TA; Hidaka A; Hoffmeister M; Huyghe JR; Jordahl K; Kawaguchi E; Keku TO; Larsson SC; Le Marchand L; Lewinger JP; Li L; Mahesworo B; Morrison J; Newcomb PA; Newton CC; Obon-Santacana M; Ose J; Pai RK; Palmer JR; Papadimitriou N; Pardamean B; Peoples AR; Pharoah PDP; Platz EA; Potter JD; Rennert G; Scacheri PC; Schoen RE; Su Y-R; Tangen CM; Thibodeau SN; Thomas DC; Ulrich CM; Um CY; van Duijnhoven FJB; Visvanathan K; Vodicka P; Vodickova L; White E; Wolk A; Woods MO; Qu C; Kundaje A; Hsu L; Gauderman WJ; Gunter MJ; Peters U
    BACKGROUND: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. METHODS: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). RESULTS: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value3-d.f.: 5.46 × 10-11) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value2-d.f.: 7.84 × 10-09). DISCUSSION: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.
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    Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.
    (American Association for the Advancement of Science, 2024-05-29) Drew DA; Kim AE; Lin Y; Qu C; Morrison J; Lewinger JP; Kawaguchi E; Wang J; Fu Y; Zemlianskaia N; Díez-Obrero V; Bien SA; Dimou N; Albanes D; Baurley JW; Wu AH; Buchanan DD; Potter JD; Prentice RL; Harlid S; Arndt V; Barry EL; Berndt SI; Bouras E; Brenner H; Budiarto A; Burnett-Hartman A; Campbell PT; Carreras-Torres R; Casey G; Chang-Claude J; Conti DV; Devall MAM; Figueiredo JC; Gruber SB; Gsur A; Gunter MJ; Harrison TA; Hidaka A; Hoffmeister M; Huyghe JR; Jenkins MA; Jordahl KM; Kundaje A; Le Marchand L; Li L; Lynch BM; Murphy N; Nassir R; Newcomb PA; Newton CC; Obón-Santacana M; Ogino S; Ose J; Pai RK; Palmer JR; Papadimitriou N; Pardamean B; Pellatt AJ; Peoples AR; Platz EA; Rennert G; Ruiz-Narvaez E; Sakoda LC; Scacheri PC; Schmit SL; Schoen RE; Stern MC; Su Y-R; Thomas DC; Tian Y; Tsilidis KK; Ulrich CM; Um CY; van Duijnhoven FJB; Van Guelpen B; White E; Hsu L; Moreno V; Peters U; Chan AT; Gauderman WJ
    Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.