| 1. |
- Zhong, Jun, et al.
(författare)
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A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer
- 2020
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 112:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). Results: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEPI) and 11 at six known risk loci (5p15.33: TERT, CLPTMIL, ZDHHCIIB; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTMIL, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.
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| 2. |
- Huang, Joyce Y., et al.
(författare)
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Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)
- 2020
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:9, s. 2394-2405
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Tidskriftsartikel (refereegranskat)abstract
- Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all p(trend) < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.
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| 3. |
- King, Sontoria D., et al.
(författare)
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Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization
- 2023
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association For Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 32:9, s. 1265-1269
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer.METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes.RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample.CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk.IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.
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| 4. |
- Robbins, Hilary A., et al.
(författare)
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Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program
- 2023
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Ingår i: Annals of Epidemiology. - : Elsevier. - 1047-2797 .- 1873-2585. ; 77, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.
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| 5. |
- Moore, Amy, et al.
(författare)
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Genetically Determined Height and Risk of Non-hodgkin Lymphoma
- 2020
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Ingår i: Frontiers in Oncology. - : FRONTIERS MEDIA SA. - 2234-943X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00-1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01-1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.
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| 6. |
- Zahed, Hana, et al.
(författare)
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Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults
- 2021
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40–80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was − 0.91 standard-deviations lower in women than men (95%CI − 0.98; − 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m2 increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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