| 1. |
- Watts, Eleanor L., et al.
(författare)
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The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 in a pooled analysis of 16,024 men from 22 studies
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 145:12, s. 3244-3256
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Tidskriftsartikel (refereegranskat)abstract
- Insulin‐like growth factors (IGFs) and insulin‐like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross‐sectional associations of these exposures with circulating concentrations of IGFs (IGF‐I and IGF‐II) and IGFBPs (IGFBP‐1, IGFBP‐2 and IGFBP‐3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22–89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGF‐I, IGF‐II and IGFBP‐3. Higher body mass index was associated with lower concentrations of IGFBP‐1 and IGFBP‐2. Taller height was associated with higher concentrations of IGF‐I and IGFBP‐3 and lower concentrations of IGFBP‐1. Smokers had higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGFBP‐3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF‐II and lower concentrations of IGF‐I and IGFBP‐2. African Americans had lower concentrations of IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 and Hispanics had lower IGF‐I, IGF‐II and IGFBP‐3 than non‐Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.
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| 2. |
- Huang, Jiaqi
(författare)
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Epidemiology and etiology of pancreatic cancer
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pancreatic cancer is one of the most devastating malignancies with an extremely high fatality, resulting that its mortality rate almost equals to incidence rate. Although primary prevention is of upmost importance, the underlying etiology of this cancer remains largely unknown. Pancreatic cancer is a heterogenetic disease, and the accumulated genetic alterations play an important role in pancreatic pathogenesis. Recent advances in next-generation sequencing have enabled comprehensive cancer genomic studies. However, clinical pancreatic cancer samples are characterized as having low tumor cellularity, as a result of an abundance of stroma in the tumor microenvironment, and this presents a big challenge for direct genomic sequencing for clinical pancreatic cancer samples. In this thesis, we aimed to enrich our knowledge of the etiology of pancreatic cancer with regard to several infectious agents and poor oral hygiene. Of note, we took the challenge to directly sequence clinical pancreatic cancer samples with a broad range of tumor cellularities, and attempted to depict its variant profile. In Study I, we retrieved all hepatitis C virus (HCV) and hepatitis B virus (HBV) infection notifications in Sweden from records in a national surveillance database at the Swedish Institutet for Infectious Disease Control (SMI) from 1990 to 2006, and followed them for pancreatic cancer occurrence by the end of 2008. The pancreatic cancer risk in the exposed population was compared with that in a matched reference population. Hazard ratios (HRs) were derived from Cox proportional hazards regression models. The main finding in this study is that the subjects with HCV infection had a 60% increased risk after adjustment for potential confounders. Therefore, the finding implied that HCV infection may be associated with a higher pancreatic cancer risk but further studies are warranted to confirm the observed association. The point estimate in this study also suggested an excessive risk among subjects with HBV infection, however, without statistical significance due to a lack of study power. In Study II, we took advantage of the population-based prevalence study of oral mucosal lesions conducted in Uppsala County in central Sweden during 1973-74. The study population was followed through linkages with the Swedish population and health registers. A total of 19 924 participants were included in the final analysis, with 126 pancreatic cancer ascertained during an average of 28.7 years of follow-up. Among all tested indicators of poor oral hygiene, we found that fewer teeth at baseline appeared to increase pancreatic cancer risk, although the relative risk estimates were not statistically significant. Among the subjects with more than 10 teeth, subjects with unacceptable dental plaque had a doubled risk of pancreatic cancer compared with those without dental plaque after controlling for potential confounding factors. Subjects with Candida-related or denture-related oral mucosal lesions, or tongue lesions, compared with those without any of the three lesions, showed a 70%, 30% and 80% increased pancreatic cancer risk, respectively. In Study III, we carried out a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, including 448 pancreatic cancer cases and their individually matched control subjects. We measured serum antibodies against Helicobacter pylori (H. pylori) and pepsinogens I and II (markers for presence of chronic corpus atrophic gastritis) by enzyme-linked immunosorbent assays. Conditional logistic regression models were used to estimate odds ratios (ORs). Overall, our results demonstrated that pancreatic cancer risk was neither associated with H. pylori seropositivity nor CagA seropositivity. On the other hand, our findings showed that presence of chronic corpus atrophic gastritis was non-significantly associated with an increased pancreatic cancer risk. Although based on small numbers, the association was particularly prominent among individuals seronegative for both H. pylori and CagA (OR=5.66; 95% confidence interval: 1.59, 20.19; p value for interaction <0.01). In Study IV, we conducted a case-only study that sourced from a population-based case-control study of pancreatic cancer in Stockholm, Sweden. This study included patients with pancreatic ductal adenocarcinoma (PDAC) who underwent resection surgery between 2007 and 2012 (n=73). Patients were followed from diagnosis until death or the end of the study. We used an Anchored Multiplex Polymerase chain reaction (AMP)-based method for profiling variants in a panel of 65 selected genes. Our findings suggested that the AMP-based next-generation sequencing method can detect variants with allelic frequencies as low as 1% given sufficient sequencing depth. KRAS G12 mutations were completely confirmed by Sanger sequencing for high-allele-frequency samples (>5%), and also fully confirmed by allele-specific PCR and digital PCR for low-allele-frequency samples (1%-5%). The results demonstrated that KRAS mutant subtype G12V is related to a worse prognosis in PDAC patients, and transversion variants are more common among smokers. In conclusion, we found that HCV, as an infectious agent, may be associated with a higher pancreatic cancer risk. Our findings also support the hypothesis that poor oral hygiene plays a key role in the development of pancreatic cancer. On the other hand, we observed a null association between H. pylori infection and pancreatic cancer risk in the western European populations, but a suggested positive association between chronic corpus atrophic gastritis and pancreatic cancer risk based on a small sample size. Further studies are warranted to verify whether severe gastric atrophy contributes to pancreatic carcinogenesis. AMP-based next generation sequencing is a sensitive and accurate method for profiling tumor variants in PDAC. Future studies with larger sample sizes are needed to explore the role of tumor variants in PDAC prognosis and the impact of environmental risk factors on tumor mutational profile.
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| 3. |
- Huang, Jiaqi, et al.
(författare)
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Helicobacter pylori infection, chronic corpus atrophic gastritis and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort : A nested case-control study
- 2017
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 140:8, s. 1727-1735
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Tidskriftsartikel (refereegranskat)abstract
- The association between H. pylori infection and pancreatic cancer risk remains controversial. We conducted a nested case-control study with 448 pancreatic cancer cases and their individually matched control subjects, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, to determine whether there was an altered pancreatic cancer risk associated with H. pylori infection and chronic corpus atrophic gastritis. Conditional logistic regression models were applied to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs), adjusted for matching factors and other potential confounders. Our results showed that pancreatic cancer risk was neither associated with H. pylori seropositivity (OR = 0.96; 95% CI: 0.70, 1.31) nor CagA seropositivity (OR = 1.07; 95% CI: 0.77, 1.48). We also did not find any excess risk among individuals seropositive for H. pylori but seronegative for CagA, compared with the group seronegative for both antibodies (OR = 0.94; 95% CI: 0.63, 1.38). However, we found that chronic corpus atrophic gastritis was non-significantly associated with an increased pancreatic cancer risk (OR = 1.35; 95% CI: 0.77, 2.37), and although based on small numbers, the excess risk was particularly marked among individuals seronegative for both H. pylori and CagA (OR = 5.66; 95% CI: 1.59, 20.19, p value for interaction < 0.01). Our findings provided evidence supporting the null association between H. pylori infection and pancreatic cancer risk in western European populations. However, the suggested association between chronic corpus atrophic gastritis and pancreatic cancer risk warrants independent verification in future studies, and, if confirmed, further studies on the underlying mechanisms.
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| 4. |
- Huang, Jiaqi, et al.
(författare)
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Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma.
- 2015
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 61:11, s. 1408-16
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Variant profiling is crucial for developing personalized treatment and elucidating the etiology of this disease.METHODS: Patients with PDAC undergoing surgery from 2007 to 2012 (n = 73) were followed from diagnosis until death or the end of the study. We applied an anchored multiplex PCR (AMP)-based next-generation sequencing (NGS) method to a panel of 65 selected genes and assessed analytical performance by sequencing a quantitative multiplex DNA reference standard. In clinical PDAC samples, detection of low-level KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations was validated by allele-specific PCR and digital PCR. We compared overall survival of patients according to KRAS mutation status by log-rank test and applied logistic regression to evaluate the association between smoking and tumor variant types.RESULTS: The AMP-based NGS method could detect variants with allele frequencies as low as 1% given sufficient sequencing depth (>1500×). Low-frequency KRAS G12 mutations (allele frequency 1%-5%) were all confirmed by allele-specific PCR and digital PCR. The most prevalent genetic alterations were in KRAS (78% of patients), TP53 (tumor protein p53) (25%), and SMAD4 (SMAD family member 4) (8%). Overall survival in T3-stage PDAC patients differed among KRAS mutation subtypes (P = 0.019). Transversion variants were more common in ever-smokers than in never-smokers (odds ratio 5.7; 95% CI 1.2-27.8).CONCLUSIONS: The AMP-based NGS method is applicable for profiling tumor variants. Using this approach, we demonstrated that in PDAC patients, KRAS mutant subtype G12V is associated with poorer survival, and that transversion variants are more common among smokers.
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| 5. |
- Playdon, Mary C., et al.
(författare)
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Metabolomics Analytics Workflow for Epidemiological Research : Perspectives from the Consortium of Metabolomics Studies (COMETS)
- 2019
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Ingår i: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 9:7
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Tidskriftsartikel (refereegranskat)abstract
- The application of metabolomics technology to epidemiological studies is emerging as a new approach to elucidate disease etiology and for biomarker discovery. However, analysis of metabolomics data is complex and there is an urgent need for the standardization of analysis workflow and reporting of study findings. To inform the development of such guidelines, we conducted a survey of 47 cohort representatives from the Consortium of Metabolomics Studies (COMETS) to gain insights into the current strategies and procedures used for analyzing metabolomics data in epidemiological studies worldwide. The results indicated a variety of applied analytical strategies, from biospecimen and data pre-processing and quality control to statistical analysis and reporting of study findings. These strategies included methods commonly used within the metabolomics community and applied in epidemiological research, as well as novel approaches to pre-processing pipelines and data analysis. To help with these discrepancies, we propose use of open-source initiatives such as the online web-based tool COMETS Analytics, which includes helpful tools to guide analytical workflow and the standardized reporting of findings from metabolomics analyses within epidemiological studies. Ultimately, this will improve the quality of statistical analyses, research findings, and study reproducibility.
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