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  • 1
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    Online Resource
    Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk
    Oxford University Press (OUP) ; 2022
    In:  JNCI: Journal of the National Cancer Institute Vol. 114, No. 8 ( 2022-08-08), p. 1135-1148
    Details
    In: JNCI: Journal of the National Cancer Institute, Oxford University Press (OUP), Vol. 114, No. 8 ( 2022-08-08), p. 1135-1148
    Abstract: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2– or 3–degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2–degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P  & lt; 1.2 × 10−4). Conclusion Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
    Type of Medium: Online Resource
    ISSN: 0027-8874 , 1460-2105
    URL: Article
    DOI: 10.1093/jnci/djac094
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 2
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    Genetically predicted circulating concentrations of micronutrients and risk of breast cancer: A Mendelian randomization study
    Wiley ; 2021
    In:  International Journal of Cancer Vol. 148, No. 3 ( 2021-02), p. 646-653
    Details
    In: International Journal of Cancer, Wiley, Vol. 148, No. 3 ( 2021-02), p. 646-653
    Abstract: What's new? The epidemiological literature reports inconsistent associations between the consumption or circulating concentrations of micro‐nutrients and breast cancer risk. Evidence from clinical trials is also lacking. Here, the authors conducted a Mendelian randomization study to investigate whether genetically‐predicted concentrations of 11 micro‐nutrients are associated with risk of breast cancer. An increased risk of overall and oestrogen‐receptor positive disease was observed for genetically‐predicted higher concentrations of magnesium that was robust to sensitivity analyses and correction for multiple comparisons.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v148.3
    DOI: 10.1002/ijc.33246
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 3
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    Development of Classic Hodgkin Lymphoma after successful treatment of primary mediastinal large b-cell lymphoma: results from a well-defined database
    Elsevier BV ; 2021
    In:  Leukemia Research Vol. 100 ( 2021-01), p. 106479-
    Details
    In: Leukemia Research, Elsevier BV, Vol. 100 ( 2021-01), p. 106479-
    Type of Medium: Online Resource
    ISSN: 0145-2126
    URL: Article
    DOI: 10.1016/j.leukres.2020.106479
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
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  • 4
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    Genome-wide interaction analysis of folate for colorectal cancer risk
    Elsevier BV ; 2023
    In:  The American Journal of Clinical Nutrition ( 2023-8)
    Details
    In: The American Journal of Clinical Nutrition, Elsevier BV, ( 2023-8)
    Type of Medium: Online Resource
    ISSN: 0002-9165
    URL: Article
    DOI: 10.1016/j.ajcnut.2023.08.010
    RVK:
    XA 18600
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 1496439-9
    SSG: 12
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  • 5
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    Abstract 817: Probing the diabetes - colorectal cancer link using gene - environment interaction analyses
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 817-817
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 817-817
    Abstract: Background: Type 2 diabetes mellitus (T2D) is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship are unclear and it is not known if the association is modified by genetic variants. To provide insights into the molecular pathways potentially linking diabetes and colorectal cancer, we undertook a large-scale gene-environment interaction analysis (GxE). Methods: We tested multiplicative statistical interactions between approximately 7 million common (allele frequency & gt;1%) genetic variants and T2D status in 31,529 colorectal cancer cases and 42,861 controls of European ancestry from 3 genetic consortia (GECCO/CCFR/CORECT). Statistical methods included traditional case-control logistic regression, case-only analyses, joint tests (2df/3df), and two-step approaches. We also explored additive and multiplicative interactions between polygenic risk score (PRS) of the known genome-wide significant loci for colorectal cancer and T2D. Results: Overall, T2D was positively associated with colorectal cancer risk [odds ratio [OR]: 1.25 (95% confidence interval [CI] : 1.14-1.36)]. A statistically significant interaction was identified between T2D status and an intronic variant in LRCH1 (rs9526201) and colorectal cancer risk using the 2-d.f. joint test (p-value:1.44x10-8). A statistically significant additive scale interaction between PRS for colorectal cancer and T2D was found (p-value: 1.8x10-10) such that the observed risk of developing colorectal cancer for individuals with T2D and a 1 standard deviation (SD) higher increment of PRS compared to non-diabetics with the lowest PRS was 0.184 more than if there was no interaction between T2D and PRS. Conclusion: These results suggest that variation in a gene related to immune function may modify the association of T2D with colorectal cancer and potentially provide novel insights into the biology underlying this relationship. Furthermore, our data show that genetic risk prediction models for CRC may need to consider non-genetic risk factors. Citation Format: Niki Dimou, Andre E. Kim, Orlagh Flanagan, Neil Murphy, Emmanouil Bouras, Peter T. Campbell, Graham Casey, Steven Gallinger, Stephen B. Gruber, Li Hsu, Mark A. Jenkins, Yi Lin, Victor Moreno, Conghui Qu, Edward Ruiz-Narvaez, Mariana C. Stern, Yu Tian, Kostas Tsilidis, W. James Gauderman, Marc J. Gunter, Ulrike Peters. Probing the diabetes - colorectal cancer link using gene - environment interaction analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 817.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-817
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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    Abstract 819: Consumption of fruits, vegetables and fiber and risk of colorectal cancer: A gene environment interaction analysis
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 819-819
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 819-819
    Abstract: Introduction: Consumption of fruits, vegetables and fiber has been associated with lower colorectal cancer (CRC) risk however, it is unclear if genetic variants can modify these associations. Methods: Within three genetic CRC consortia including up to 76,157 participants (32,859 cases and 43,298 controls) of European descent: the Colorectal Cancer Family Registry (CCFR), the Colorectal Cancer Transdisciplinary (CORECT) Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), one-step [logistic regression case-control analysis and joint two- and three-degrees of freedom (DF) tests] and two-step methods were implemented to identify novel and biologically plausible gene-environment interactions. Results: Fruits, vegetables and fiber consumption were inversely associated with CRC with odds ratios per quartile increase of 0.89 [95% confidence interval (CI): 0.86, 0.92], 0.91 (95% CI: 0.88, 0.94) and 0.86 (95% CI: 0.84, 0.89) respectively. The logistic regression analysis identified significant interaction effects between rs142981275 adjacent to the ACOT1 gene and fruits consumption (pval:1.91E-8) and the 2DF test, which jointly considers G and GxE effects, also identified this SNP. The 3DF test also considers G and GxE information and further revealed four loci associated with CRC risk, in the genes NEGR1(rs1620977), ZRANB3 (rs1561277), MCM6 (rs4988235), R3HDM1(rs12465802) (all pval: & lt;5E-8) out of which rs1620977 and rs12465802 were the leading independent variants. For vegetables, the 3DF test identified significant interaction effects in the DCBLD1 gene (rs4946259; pval:1.44E-8). Finally, no significant interactions were observed for any genetic variant and fiber consumption. The 2-step approach did not identify additional interactions either. Conclusion: This study identified statistically significant interactions between several genetic variants and the consumption of fruits and vegetables with CRC risk. Further research is needed to elucidate the exact mechanisms through which these interactions might influence CRC risk. Citation Format: Nikos Papadimitriou, Akihisa Hidaka, Andre Kim, Niki Dimou, Neil Murphy, Sonja I. Berndt, David Conti, Peter T. Campbell, Graham Casey, Jane C. Figueiredo, Konstantinos K. Tsilidis, Stephen B. Gruber, Sophia Harlid, Yi Lin, Victor Moreno, Lori C. Sakoda, Virginia D. Obrero, Li Hsu, William J. Gauderman, Marc Gunter, Ulrike Peters. Consumption of fruits, vegetables and fiber and risk of colorectal cancer: A gene environment interaction analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 819.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-819
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis
    Springer Science and Business Media LLC ; 2022
    In:  BMC Medicine Vol. 20, No. 1 ( 2022-12)
    Details
    In: BMC Medicine, Springer Science and Business Media LLC, Vol. 20, No. 1 ( 2022-12)
    Abstract: Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR. Methods Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated ( P 〈 5.0 × 10 −8 ) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR. Results In MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10 −31 ), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10 −12 ), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10 −9 ), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10 −7 ) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10 −4 ) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10 −2 ) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10 −3 ), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10 −8 ) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10 −2 ) in the relationship between BMI and endometrial cancer risk. Conclusions Our comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.
    Type of Medium: Online Resource
    ISSN: 1741-7015
    URL: Article
    DOI: 10.1186/s12916-022-02322-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 8
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    Abstract 818: Association of polygenic risk score and menopausal hormone therapy for colorectal cancer risk
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 818-818
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 818-818
    Abstract: Background and objective Genetic predisposition and menopausal hormone therapy (MHT) are established risk and preventive factors for colorectal cancer (CRC), respectively. We aimed to evaluate the joint associations of a polygenic risk score (PRS) and MHT on CRC risk for informing CRC prevention. Methods We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent from 38 studies. MHT use was assessed as the use of any MHT, estrogen-only (E-only) or combined estrogen-progestogen (E+P) therapy at reference time. A PRS based on 141 genetic variants previously identified by genome-wide association studies of CRC was modelled as categorical variable in quartiles and also as per-standard deviation difference between PRS and minimum of PRS [(PRS-min(PRS))/SD(PRS)] (PRS.minsd). Multiplicative interaction between PRS and MHT was evaluated using standard logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). Results The use of any MHT as well as E+P and E-only were associated with reduced CRC risk (Odds ratio [OR] 0.70, 0.71, 0.65, respectively). PRS was associated with increased CRC risk, whether as continuous variable (PRS.minsd) (OR 1.53) or in quartiles (OR 1.49, 1.92, 2.87, respectively). We identified statistically significant negative multiplicative interaction (OR: 0.92; 95%CI: 0.87, 0.98) as well as negative additive interaction (RERI: -0.13; 95%CI: -0.15, -0.10) between PRS.minsd and any MHT use. Results were limited to additive interactions with PRS.minsd for E-only use (RERI: -0.14; 95%CI: -0.18, -0.11) and E+P use (RERI: -0.12; 95%CI: -0.16, -0.08). The magnitude of negative additive interactions increased with higher quartiles of PRS for all MHT variables and was consistently significant for the highest quartile compared to the lowest quartile of PRS for any MHT use (RERI: -0.78; 95%CI: -1.03, -0.52), E-only use (RERI: -0.78; 95%CI: -1.18, -0.39), and also E+P use (RERI: -0.53; 95%CI: -0.96, -0.10). Negative multiplicative interaction was also observed for higher PRS quartiles of all MHT variables but significant only for the highest quartile with E-only use (OR: 0.73; 95%CI: 0.55, 0.97). These negative interactions on both multiplicative and additive scales indicate that MHT has a relatively more protective effect on CRC risk for those women with larger PRS scores. For example, compared to women in the lowest PRS quartile with no MHT use, the risk of CRC for women in higher quartiles of PRS was more strongly reduced with MHT use (ORPRS.Q3+noMHT: 1.93 vs ORPRS.Q3+MHT: 1.38, OR MHT/noMHT in PRS.Q3: 0.71; ORPRS.Q4+noMHT: 2.81 vs ORPRS.Q4+MHT: 1.77, OR MHT/noMHT in PRS.Q4: 0.63). Conclusions The protective effect of MHT use on the risk of CRC is stronger in women with higher genetic risk. Risk prediction models incorporating PRS may need to account for potential effect modification by non-genetic risk factors. Citation Format: Yu Tian, Yi Lin, Andre E. Kim, Stephanie A. Bien, Polly A. Newcomb, Graham Casey, Elizabeth A. Platz, Loic Le Marchand, Peter T. Campbell, Hermann Brenner, Michael Hoffmeister, Feng Guo, Xuechen Chen, Marc J. Gunter, Niki Dimou, Stephen B. Gruber, Andrew T. Chan, Amit D. Joshi, Sonja I. Berndt, Emily White, Victor Moreno, Ross L. Prentice, Ulrike Peters, William Gauderman, Li Hsu, Jenny Chang-Claude. Association of polygenic risk score and menopausal hormone therapy for colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 818.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-818
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 9
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    Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 31, No. 5 ( 2022-05-04), p. 1077-1089
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 31, No. 5 ( 2022-05-04), p. 1077-1089
    Abstract: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers ( & gt;28 g/day) with light-to-moderate drinkers (1–28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 & gt; 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose–response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype = 1.22; 95% CI, 1.14–1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-21-1003
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 10
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    Cigarette Smoking and Endometrial Cancer Risk: Observational and Mendelian Randomization Analyses
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 31, No. 9 ( 2022-09-02), p. 1839-1848
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 31, No. 9 ( 2022-09-02), p. 1839-1848
    Abstract: Current epidemiologic evidence indicates that smoking is associated with a lower endometrial cancer risk. However, it is unknown if this association is causal or confounded. To further elucidate the role of smoking in endometrial cancer risk, we conducted complementary observational and Mendelian randomization (MR) analyses. Methods: The observational analyses included 286,415 participants enrolled in the European Prospective Investigation into Cancer and Nutrition and 179,271 participants in the UK Biobank, and multivariable Cox proportional hazards models were used. In two-sample MR analyses, genetic variants robustly associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants) were selected and their association with endometrial cancer risk (12,906 cancer/108,979 controls from the Endometrial Cancer Association Consortium) was examined. Results: In the observational analysis, lifetime amount of smoking and ever having smoked regularly were associated with a lower endometrial cancer risk. In the MR analysis accounting for body mass index, a genetic predisposition to a higher lifetime amount of smoking was not associated with endometrial cancer risk (OR per 1-SD increment: 1.15; 95% confidence interval: 0.91–1.44). Genetic predisposition to ever having smoked regularly was not associated with risk of endometrial cancer. Conclusions: Smoking was inversely associated with endometrial cancer in the observational analyses, although unsupported by the MR. Additional studies are required to better understand the possible confounders and mechanisms underlying the observed associations between smoking and endometrial cancer. Impact: The results from this analysis indicate that smoking is unlikely to be causally linked with endometrial cancer risk.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-21-1176
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 1153420-5
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