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- Catalano, Calogerina, et al.
(författare)
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Epistatic effect of TLR3 and cGAS-STING-IKKε-TBK1-IFN signaling variants on colorectal cancer risk
- 2020
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 9:4, s. 1473-1484
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The TLR3/cGAS-STING-IFN signaling has recently been reported to be disturbed in colorectal cancer due to deregulated expression of the genes involved. Our study aimed to investigate the influence of potential regulatory variants in these genes on the risk of sporadic colorectal cancer (CRC) in a Czech cohort of 1424 CRC patients and 1114 healthy controls. Methods: The variants in the TLR3, CGAS, TMEM173, IKBKE, and TBK1 genes were selected using various online bioinformatic tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, SIFT, PolyPhen2, and miRNA prediction tools. Results: Logistic regression analysis adjusted for age and sex detected a nominal association between CRC risk and three variants, CGAS rs72960018 (OR: 1.68, 95% CI: 1.11-2.53, P-value =.01), CGAS rs9352000 (OR: 2.02, 95% CI: 1.07-3.84, P-value =.03) and TMEM173 rs13153461 (OR: 1.53, 95% CI: 1.03-2.27, P-value =.03). Their cumulative effect revealed a threefold increased CRC risk in carriers of 5-6 risk alleles compared to those with 0-2 risk alleles. Epistatic interactions between these genes and the previously genotyped IFNAR1, IFNAR2, IFNA, IFNB, IFNK, IFNW, IRF3, and IRF7 genes, were computed to test their effect on CRC risk. Overall, we obtained nine pair-wise interactions within and between the CGAS, TMEM173, IKBKE, and TBK1 genes. Two of them remained statistically significant after Bonferroni correction. Additional 52 interactions were observed when IFN variants were added to the analysis. Conclusions: Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management.
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- Cook, Daniel John, 1986, et al.
(författare)
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Molecular natural history of breast cancer: Leveraging transcriptomics to predict breast cancer progression and aggressiveness
- 2020
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 9:10, s. 3551-3562
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Tidskriftsartikel (refereegranskat)abstract
- Cancer Medicine published by John Wiley & Sons Ltd. Background: Characterizing breast cancer progression and aggressiveness relies on categorical descriptions of tumor stage and grade. Interpreting these categorical descriptions is challenging because stage convolutes the size and spread of the tumor and no consensus exists to define high/low grade tumors. Methods: We address this challenge of heterogeneity in patient-specific cancer samples by adapting and applying several tools originally created for understanding heterogeneity and phenotype development in single cells (specifically, single-cell topological data analysis and Wanderlust) to create a continuous metric describing breast cancer progression using bulk RNA-seq samples from individual patient tumors. We also created a linear regression-based method to predict tumor aggressiveness in vivo from bulk RNA-seq data. Results: We found that breast cancer proceeds along three convergent phenotype trajectories: luminal, HER2-enriched, and basal-like. Furthermore, 31 296 genes (for luminal cancers), 17 827 genes (for HER2-enriched), and 18 505 genes (for basal-like) are dynamically differentially expressed during breast cancer progression. Across progression trajectories, our results show that expression of genes related to ADP-ribosylation decreased as tumors progressed (while PARP1 and PARP2 increased or remained stable), suggesting the potential for a differential response to PARP inhibitors based on cancer progression. Additionally, we developed a 132-gene expression regression equation to predict mitotic index and a 23-gene expression regression equation to predict growth rate from a single breast cancer biopsy. Conclusion: Our results suggest that breast cancer dynamically changes during disease progression, and growth rate of the cancer cells is associated with distinct transcriptional profiles.
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- Deb, Suryyani, et al.
(författare)
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Varying effects of tyrosine kinase inhibitors on platelet function : A need for individualized CML treatment to minimize the risk for hemostatic and thrombotic complications?
- 2020
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Ingår i: Cancer Medicine. - : John Wiley & Sons. - 2045-7634. ; 9:1, s. 313-323
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Tidskriftsartikel (refereegranskat)abstract
- Since their introduction, tyrosine kinase inhibitors (TKIs, eg, imatinib, nilotinib, dasatinib, bosutinib, ponatinib) have revolutionized the treatment of chronic myeloid leukemia (CML). However, long-term treatment with TKIs is associated with serious adverse events including both bleeding and thromboembolism. Experimental studies have shown that TKIs can cause platelet dysfunction. Herein, we present the first side-by-side investigation comparing the effects of currently used TKIs on platelet function and thrombin generation when used in clinically relevant concentrations. A flow cytometry multiparameter protocol was used to study a range of significant platelet activation events (fibrinogen receptor activation, alpha granule, and lysosomal exocytosis, procoagulant membrane exposure, and mitochondrial permeability changes). In addition, thrombin generation was measured in the presence of TKIs to assess the effects on global hemostasis. Results show that dasatinib generally inhibited platelet function, while bosutinib, nilotinib, and ponatinib showed less consistent effects. In addition to these general trends for each TKI, we observed a large degree of interindividual variability in the effects of the different TKIs. Interindividual variation was also observed when blood from CML patients was studied ex vivo with whole blood platelet aggregometry, free oscillation rheometry (FOR), and flow cytometry. Based on the donor responses in the side-by-side TKI study, a TKI sensitivity map was developed. We propose that such a sensitivity map could potentially become a valuable tool to help in decision-making regarding the choice of suitable TKIs for a CML patient with a history of bleeding or atherothrombotic disease.
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- Larsson, Susanna C., et al.
(författare)
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Insulin-like growth factor-1 and site-specific cancers : A Mendelian randomization study.
- 2020
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 9:18, s. 6836-6842
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor-1 (IGF-1) is involved in several processes relevant to carcinogenesis. We used 416 single-nucleotide polymorphisms robustly associated with serum IGF-1 levels to assess the potential causal associations between this hormone and site-specific cancers through Mendelian randomization. Summary-level genetic association estimates for prostate, breast, ovarian, and lung cancer were obtained from large-scale consortia including individuals of European-descent. Furthermore, we estimated genetic associations with 14 site-specific cancers in European-descent individuals in UK Biobank. Supplementary analyses were conducted for six site-specific cancers using summary-level data from the BioBank Japan Project. Genetically predicted serum IGF-1 levels were associated with colorectal cancer. The odds ratio (OR) per standard deviation increase of IGF-1 levels was 1.11 (95% confidence interval [CI] 1.01-1.22; P = .03) in UK Biobank and 1.22 (95% CI 1.09-1.36; P = 3.9 × 10-4 ) in the BioBank Japan Project. For prostate cancer, the corresponding OR was 1.10 (95% CI 1.01-1.21; P = .04) in UK Biobank, 1.03 (95% CI 0.97-1.09; P = .41) in the prostate cancer consortium, and 1.08 (95% CI 0.95-1.22; P = .24) in the BioBank Japan Project. For breast cancer, the corresponding OR was 0.99 (95% CI 0.92-1.07; P = .85) in UK Biobank and 1.08 (95% CI 1.02-1.13; P = 4.4 × 10-3 ) in the Breast Cancer Association Consortium. There was no statistically significant association between genetically predicted IGF-1 levels and 14 other cancers. This study found some support for a causal association between elevated serum IGF-1 levels and increased risk of colorectal cancer. There was inconclusive or no evidence of a causal association of IGF-1 levels with prostate, breast, and other cancers.
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- Latini, Francesco, 1982-, et al.
(författare)
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Differences in the preferential location and invasiveness of diffuse low-grade gliomas and their impact on outcome
- 2020
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 9:15, s. 5446-5458
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Low-grade gliomas (LGGs) are primary diffuse slow-growing brain tumors derived from glial cells. The management of these tumors is dependent on their location, which often harbors eloquent areas. We retrospectively recorded the location of diffuse gliomas to identify whether specific differences exist between the histological types.METHODS: We analyzed 102 patients with previous histological diagnosis of WHO-II astrocytomas (62) and WHO-II oligodendrogliomas (40) according to WHO-2016 classification. MRI sequences (T2-FLAIR) were used for tumor volume segmentation and to create a frequency map of their locations within the Montreal Neurological Institute (MNI) space. The Brain-Grid (BG) system (standardized radiological tool of intersected lines according to anatomical landmarks) was created and merged with a tractography atlas for infiltration analysis.RESULTS: Astrocytomas frequently infiltrated association and projection white matter pathways within fronto-temporo-insular regions on the left side. Oligodendrogliomas infiltrated larger white matter networks (association-commissural-projection) of the frontal lobe bilaterally. A critical number of infiltrated BG voxels (7 for astrocytomas, 10 for oligodendrogliomas) significantly predicted shorter overall survival (OS) in both groups. Bilateral tumor extension in astrocytomas and preoperative tumor volume in oligodendrogliomas were independent prognostic factors for shorter OS.CONCLUSIONS: Astrocytomas and oligodendrogliomas differ in preferential location, and this has an impact on the type and the extent of white matter involvement. The number of BG voxels infiltrated reflected different tumor invasiveness and its impact on OS in both groups. All this new information may be valuable in neurosurgical oncology to classify and plan treatment for patients with diffuse gliomas.
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| 10. |
- Russell, Beth, et al.
(författare)
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A mediation analysis to explain socio-economic differences in bladder cancer survival
- 2020
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Ingår i: Cancer Medicine. - : John Wiley & Sons. - 2045-7634. ; 9:20, s. 7477-7487
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: This study aims to disentangle heterogeneity in the survival of bladder cancer (BC) patients of different socioeconomic status (SES) by identifying potential mediators of the relationship.Methods: The Bladder Cancer Database Sweden (BladderBaSe) was used to select patients diagnosed between 1997 and 2014 with Tis/Ta-T4 disease. The education level was used as a proxy for SES. Accelerated failure time models were used to investigate the association between SES and survival. Mediation analysis was used to investigate potential mediators of the association also accounting for interaction.Results: The study included 37 755 patients from the BladderBaSe. Patients diagnosed with both non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) who had high SES were found to have increased overall and BC-specific survival, when compared to those with low SES. In the NMIBC patients, Charlson Comorbidity Index was found to mediate this relationship by 10% (percentage of the total effect explained by the mediator) and hospital type by 4%. The time from referral to TURBT was a considerable mediator (14%) in the MIBC patients only.Conclusions: Mediation analysis suggests that the association between SES and BC survival can be explained by several factors. The mediators identified were not, however, able to fully explain the theoretical causal pathway between SES and survival, therefore, future studies should also include the investigation of other possible mediators to help explain this relationship further. These results highlight the importance of standardization of clinical care across SES groups.
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