| 1. |
- Anantharaman, Devasena, et al.
(författare)
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Combined effects of smoking and HPV16 in oropharyngeal cancer
- 2016
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Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 45:3, s. 752-761
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although smoking and HPV infection are recognized as important risk factors for oropharyngeal cancer, how their joint exposure impacts on oropharyngeal cancer risk is unclear. Specifically, whether smoking confers any additional risk to HPV-positive oropharyngeal cancer is not understood.Methods: Using HPV serology as a marker of HPV-related cancer, we examined the interaction between smoking and HPV16 in 459 oropharyngeal (and 1445 oral cavity and laryngeal) cancer patients and 3024 control participants from two large European multicentre studies. Odds ratios and credible intervals [CrI], adjusted for potential confounders, were estimated using Bayesian logistic regression.Results: Both smoking [odds ratio (OR [CrI]: 6.82 [4.52, 10.29]) and HPV seropositivity (OR [CrI]: 235.69 [99.95, 555.74]) were independently associated with oropharyngeal cancer. The joint association of smoking and HPV seropositivity was consistent with that expected on the additive scale (synergy index [CrI]: 1.32 [0.51, 3.45]), suggesting they act as independent risk factors for oropharyngeal cancer.Conclusions: Smoking was consistently associated with increase in oropharyngeal cancer risk in models stratified by HPV16 seropositivity. In addition, we report that the prevalence of oropharyngeal cancer increases with smoking for both HPV16-positive and HPV16-negative persons. The impact of smoking on HPV16-positive oropharyngeal cancer highlights the continued need for smoking cessation programmes for primary prevention of head and neck cancer.
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| 2. |
- Antoniou, Antonis C., et al.
(författare)
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A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:10, s. 885-892
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Tidskriftsartikel (refereegranskat)abstract
- Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P-trend = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P-trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P-trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P-trend = 1.1 x 10(-7)).
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| 3. |
- Archambault, Alexi N., et al.
(författare)
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Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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| 4. |
- Bernatsky, Sasha, et al.
(författare)
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Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma
- 2017
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Ingår i: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE.
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| 5. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:8, s. 868-U202
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 x 10(-14)), 18q21.33 (BCL2, P = 7.76 x 10(-11)), 11p15.5 (C11orf21, P = 2.15 x 10(-10)), 4q25 (LEF1, P = 4.24 x 10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 x 10(-9)), 9p21.3 (CDKN2B-AS1, P = 1.27 x 10(-8)), 18q21.32 (PMAIP1, P = 2.51 x 10(-8)), 15q15.1 (BMF, P = 2.71 x 10(-10)) and 2p22.2 (QPCT, P = 1.68 x 10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 x 10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 x 10(-8)) and 5p15.33 (TERT, P = 1.92 x 10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
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| 6. |
- Bien, Stephanie A., et al.
(författare)
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
- 2019
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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| 7. |
- Cerhan, James R., et al.
(författare)
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Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:11, s. 1233-1238
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Tidskriftsartikel (refereegranskat)abstract
- Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 x 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 x 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 x 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 x 10(-13) and 3.63 x 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
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| 8. |
- Christakoudi, Sofia, et al.
(författare)
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Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition
- 2020
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 146:10, s. 2680-2693
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have reported associations of hypertension with cancer, but not all results were conclusive. We examined the association of systolic (SBP) and diastolic (DBP) blood pressure with the development of incident cancer at all anatomical sites in the European Prospective Investigation into Cancer and Nutrition (EPIC). Hazard ratios (HRs) (95% confidence intervals) were estimated using multivariable Cox proportional hazards models, stratified by EPIC-participating center and age at recruitment, and adjusted for sex, education, smoking, body mass index, physical activity, diabetes and dietary (in women also reproductive) factors. The study included 307,318 men and women, with an average follow-up of 13.7 (standard deviation 4.4) years and 39,298 incident cancers. We confirmed the expected positive association with renal cell carcinoma: HR = 1.12 (1.08-1.17) per 10 mm Hg higher SBP and HR = 1.23 (1.14-1.32) for DBP. We additionally found positive associations for esophageal squamous cell carcinoma (SCC): HR = 1.16 (1.07-1.26) (SBP), HR = 1.31 (1.13-1.51) (DBP), weaker for head and neck cancers: HR = 1.08 (1.04-1.12) (SBP), HR = 1.09 (1.01-1.17) (DBP) and, similarly, for skin SCC, colon cancer, postmenopausal breast cancer and uterine adenocarcinoma (AC), but not for esophageal AC, lung SCC, lung AC or uterine endometroid cancer. We observed weak inverse associations of SBP with cervical SCC: HR = 0.91 (0.82-1.00) and lymphomas: HR = 0.97 (0.93-1.00). There were no consistent associations with cancers in other locations. Our results are largely compatible with published studies and support weak associations of blood pressure with cancers in specific locations and morphologies.
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| 9. |
- Christakoudi, Sofia, et al.
(författare)
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Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
- 2021
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 148:7, s. 1637-1651
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.
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| 10. |
- Crowe, Francesca L., et al.
(författare)
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Circulating Fatty Acids and Prostate Cancer Risk : Individual Participant Meta-Analysis of Prospective Studies
- 2014
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 106:9, s. dju240-
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Forskningsöversikt (refereegranskat)abstract
- BackgroundIndividual studies have suggested that some circulating fatty acids are associated with prostate cancer risk, but have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease.MethodsPrincipal investigators of prospective studies on circulating fatty acids and prostate cancer were invited to collaborate. Investigators provided individual participant data on circulating fatty acids (weight percent) and other characteristics of prostate cancer cases and controls. Prostate cancer risk by study-specific fifths of 14 fatty acids was estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided.ResultsFive thousand and ninety-eight case patients and 6649 control patients from seven studies with an average follow-up of 5.1 (SD = 3.3) years were included. Stearic acid (18: 0) was inversely associated with total prostate cancer (odds ratio [OR] Q5 vs Q1 = 0.88, 95% confidence interval [CI] = 0.78 to 1.00, P-trend = .043). Prostate cancer risk was, respectively, 14% and 16% greater in the highest fifth of eicosapentaenoic acid (20:5n-3) (OR = 1.14, 95% CI = 1.01 to 1.29, P-trend = .001) and docosapentaenoic acid (22: 5n-3) (OR = 1.16, 95% CI = 1.02 to 1.33, P-trend = .003), but in each case there was heterogeneity between studies (P = .022 and P < .001, respectively). There was heterogeneity in the association between docosapentaenoic acid and prostate cancer by grade of disease (P = .006); the association was statistically significant for low-grade disease but not high-grade disease. The remaining 11 fatty acids were not statistically associated with total prostate cancer risk.ConclusionThere was no strong evidence that circulating fatty acids are important predictors of prostate cancer risk. It is not clear whether the modest associations of stearic, eicosapentaenoic, and docosapentaenoic acid are causal.
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