| 1. |
- Bengtsson, Daniel, 1975-, et al.
(författare)
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Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort
- 2017
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : OXFORD UNIV PRESS INC. - 0021-972X .- 1945-7197. ; 102:11, s. 3928-3932
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Tidskriftsartikel (refereegranskat)abstract
- Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patients germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.
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| 2. |
- Chatziioannou, Aristotelis, et al.
(författare)
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Blood-based omic profiling supports female susceptibility to tobacco smoke-induced cardiovascular diseases
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- We recently reported that differential gene expression and DNA methylation profiles in blood leukocytes of apparently healthy smokers predicts with remarkable efficiency diseases and conditions known to be causally associated with smoking, suggesting that blood-based omic profiling of human populations may be useful for linking environmental exposures to potential health effects. Here we report on the sex-specific effects of tobacco smoking on transcriptomic and epigenetic features derived from genome-wide profiling in white blood cells, identifying 26 expression probes and 92 CpG sites, almost all of which are affected only in female smokers. Strikingly, these features relate to numerous genes with a key role in the pathogenesis of cardiovascular disease, especially thrombin signaling, including the thrombin receptors on platelets F2R (coagulation factor II (thrombin) receptor; PAR1) and GP5 (glycoprotein 5), as well as HMOX1 (haem oxygenase 1) and BCL2L1 (BCL2-like 1) which are involved in protection against oxidative stress and apoptosis, respectively. These results are in concordance with epidemiological evidence of higher female susceptibility to tobacco-induced cardiovascular disease and underline the potential of blood-based omic profiling in hazard and risk assessment.
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| 3. |
- Georgiadis, Panagiotis, et al.
(författare)
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Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis
- 2017
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance.RESULTS: We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0-15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B-cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to-diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while differentially expressed genes include, among others, multiple genes related to WNT signaling as well as the miRNAs miR-150-5p and miR-155-5p.CONCLUSIONS: Our findings demonstrate the presence in prediagnostic blood of future CLL patients, more than 10 years before diagnosis, of CLL-like cells which evolve as preclinical disease progresses, and point to early molecular alterations with a pathogenetic potential.
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| 4. |
- Johansson, Gunnar, et al.
(författare)
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Molecular classification of malignat glioma
- 2017
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 19:S3, s. 88-88
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Tidskriftsartikel (refereegranskat)abstract
- Background: Malignant glioma are devastating tumors with poor prognosis. In recent years, the classification of glioma have evolved greatly due to exploration of several molecular tools in addition to the traditional immunohistochemistry.Methods: To further evolve this classification, we thoroughly characterized the molecular and histological signature of 367 glioma patients from Sweden. We first obtained the full medical history and histological classification, along with matched blood samples and unstained tissue slides. We have performed extensive molecular characterization using genome wide association studies, methylation arrays and telomere length assays. We have extended the classification to include IDH1 mutations, chromosome 1p/19q co-deletion, EGFR amplification as well as the expression of two novel cell signaling regulators. The statistical analysis is ongoing and will reveal how well we can classify the tumors by combining the above mentioned techniques. Results: As expected we found EGFR upregulation in almost 50% of the patients with glioblastoma and one third of patients with anaplastic astrocytoma and anaplastic oligodendroglioma. No EGFR expression was found in any patient with low grade glioma. In consistence with previous studies 70% of the IDH1 mutated oligodendroglioma had 1p/19q co-deletion. In the IDH1 wildtype oligodendroglioma, about 50% of the low grade tumors had 1p/19q co-deletion. Interestingly, we found complete 1p/19q co-deletion in about 10% of the IDH1 wild type glioblastoma.Conclusion: Today, 1p/19q co-deletion is normally only studied in suspected oligodendroglioma and not in all types of glioma. Pending the clinical relevance of the 1p/19q co-deleted glioblastoma, it might be wise to expand the 1p/19q classification by including all types of glioma.
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| 5. |
- Lupo, P., et al.
(författare)
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Perinatal and Familial Risk Factors for Soft-Tissue Sarcomas in Children, Adolescents, and Young Adults : A Population-Based Birth Cohort Study, Sweden, 1973-2012
- 2017
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Ingår i: Pediatric Blood & Cancer. - : John Wiley & Sons. - 1545-5009 .- 1545-5017. ; 64, s. S4-S5
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background/Objectives: Perinatal factors have been associated with soft-tissue sarcomas (STS) in case-control studies. However, (1) the specific contributions of factors including fetal growth remain unknown, (2) these factors have not been examined in large cohort studies, and (3) few assessments have evaluated risk in specific STS subtypes. Therefore, we sought to identify the role of perinatal and familial factors on the risk of STS in a large population-based birth cohort. Design/Methods: We identified 5,063,499 individuals in the Swedish Birth Registry born during 1973-2012. Subjects were linked to the Swedish Cancer Registry, where incident STS cases were identified. We evaluated perinatal and familial factors obtained from Statistics Sweden, including: fetal growth, gestational age, presence of a congenital anomaly, and parental age. Poisson regression was used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for associations between selected factors and STS overall, as well as by common subtypes. Results: There were 673 children, adolescents, and young adults diagnosed with STS in 77.5 million person-years of follow-up. Having a congenital anomaly was associated with STS risk (IRR=1.70, 95% CI: 1.23-2.35). This association was stronger (IRR=2.89, 95% CI: 1.25-6.70) in more recent years (2000-2012). High fetal growth was also associated with STS during the same time period (IRR=1.87, 95% CI: 1.06-3.30). Being born preterm (35 years) was inversely associated with the risk of developing synovial sarcoma (IRR=0.50, 95% CI: 0.26-0.94). Conclusions: In this cohort study, those with congenital anomalies and other adverse birth outcomes were more likely to develop a STS compared to their unaffected contemporaries. These associations may point to disrupted developmental pathways influencing the risk of STS. Our findings could implicate novel mechanisms underlying susceptibility to STS and may inform future surveillance, prevention, and treatment efforts.
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| 6. |
- Melin, Beatrice S., et al.
(författare)
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Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:5, s. 789-794
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 x 10(-9), odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 x 10(-10), OR = 1.24), 16p13.3 (rs2562152; P = 1.93 x 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 x 10(-11), OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 x 10(-10), OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 x 10(-9), OR = 1.19), 1q44 (rs12076373; P = 2.63 x 10(-10), OR = 1.23), 2q33.3 (rs7572263; P = 2.18 x 10(-10), OR = 1.20), 3p14.1 (rs11706832; P = 7.66 x 10(-9), OR = 1.15), 10q24.33 (rs11598018; P = 3.39 x 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 x 10(-10), OR = 1.16), 14q12 (rs10131032; P = 5.07 x 10(-11), OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 x 10(-9), OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.
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| 7. |
- Perez-Cornago, Aurora, et al.
(författare)
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Prediagnostic circulating concentrations of plasma insulin-like growth factor-I and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition
- 2017
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Ingår i: International Journal of Cancer. - : WILEY-BLACKWELL. - 0020-7136 .- 1097-0215. ; 140:5, s. 1111-1118
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor (IGF)-I has cancer promoting activities. However, the hypothesis that circulating IGF-I concentration is related to risk of lymphoma overall or its subtypes has not been examined prospectively. IGF-I concentration was measured in pre-diagnostic plasma samples from a nested case-control study of 1,072 cases of lymphoid malignancies and 1,072 individually matched controls from the European Prospective Investigation into Cancer and Nutrition. Odds ratios (ORs) and confidence intervals (CIs) for lymphoma were calculated using conditional logistic regression. IGF-I concentration was not associated with overall lymphoma risk (multivariable-adjusted OR for highest versus lowest third = 0.77 [95% CI = 0.57-1.03], p(trend) = 0.06). There was no statistical evidence of heterogeneity in this association with IGF-I by sex, age at blood collection, time between blood collection and diagnosis, age at diagnosis, or body mass index (pheterogeneity for all >= 0.05). There were no associations between IGF-I concentration and risk for specific BCL subtypes, T-cell lymphoma or Hodgkin lymphoma, although number of cases were small. In this European population, IGF-I concentration was not associated with risk of overall lymphoma. This study provides the first prospective evidence on circulating IGF-I concentrations and risk of lymphoma. Further What's new? Insulin-like growth factor I does not appear to influence lymphoma risk, according to new results. IGF-I can promote some cancers, but there hasn't been a prospective epidemiological study examining the link between IGF-I concentration and lymphoma risk. To uncover a link, these authors arranged a NESTED case-control study with participants from the European Prospective Investigation into Cancer and Nutrition (EPIC). They tested for IGF-I in pre-diagnosis samples and found no association between the factor and overall lymphoma risk, nor with any subtype, although the number of cases was small for each subtype, and further studies are necessary.
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| 8. |
- Sjöström, Olle, et al.
(författare)
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Colonoscopic surveillance : a cost-effective method to prevent hereditary and familial colorectal cancer
- 2017
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 52:9, s. 1002-1007
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Approximately 20-30% of all colorectal cancer (CRC) cases may have a familial contribution. The family history of CRC can be prominent (e.g., hereditary colorectal cancer (HCRC)) or more moderate (e.g., familial colorectal cancer (FCRC)). For family members at risk, colonoscopic surveillance is a well-established method to prevent both HCRC and FCRC, although the evidence for the exact procedures of the surveillance is limited. Surveillance can come at a high price if individuals are frequently examined, as this may result in unnecessary colonoscopies in relation to actual risk for CRC. This study analyses the cost-effectiveness of a surveillance programme implemented in the Northern Sweden Health Care Region.Methods: The study includes 259 individuals prospectively recorded in the colonoscopic surveillance programme registry at the Cancer Prevention Clinic, Umea University Hospital. We performed a cost-utility analysis with a contrafactual design: we compared observed costs and loss of quality-adjusted life years (QALYs) due to CRC with the surveillance programme to an expected outcome without surveillance. The main measure was the incremental cost-effectiveness ratio (ICER) between surveillance and non-surveillance. Scenario analysis was used to explore uncertainty.Results: The ICER between surveillance and non-surveillance in the base model was 3596Euro/QALY. The ICER varied from -4620Euro in the best-case scenario to 33,779Euro in the worst-case scenario.Conclusion: Colonoscopic surveillance is a very cost-effective method to prevent HCRC and FCRC compared to current thresholds for cost-effectiveness and other cancer preventive interventions.
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| 9. |
- Späth, Florentin, et al.
(författare)
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Biomarker Dynamics in B-cell Lymphoma : A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis
- 2017
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 77:6, s. 1408-1415
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Tidskriftsartikel (refereegranskat)abstract
- The B-cell activation markers CXCL13, sCD23, (S)CD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of markerdisease association hampers interpretation. In this study, we identified 170 individuals who had donated two prediagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lympho-ma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope - 28, Ptrend(-)7.279 x 10 (-10)). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Furthermore, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients.
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