| 1. |
- Abdulla, Maysaa, et al.
(författare)
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Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma
- 2020
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Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 95:1, s. 57-67
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Tidskriftsartikel (refereegranskat)abstract
- The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.
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| 2. |
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| 3. |
- Andersson-Evelönn, Emma, 1983-, et al.
(författare)
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Combining epigenetic and clinicopathological variables improves specificity in prognostic prediction in clear cell renal cell carcinoma
- 2020
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Metastasized clear cell renal cell carcinoma (ccRCC) is associated with a poor prognosis. Almost one-third of patients with non-metastatic tumors at diagnosis will later progress with metastatic disease. These patients need to be identified already at diagnosis, to undertake closer follow up and/or adjuvant treatment. Today, clinicopathological variables are used to risk classify patients, but molecular biomarkers are needed to improve risk classification to identify the high-risk patients which will benefit most from modern adjuvant therapies. Interestingly, DNA methylation profiling has emerged as a promising prognostic biomarker in ccRCC. This study aimed to derive a model for prediction of tumor progression after nephrectomy in non-metastatic ccRCC by combining DNA methylation profiling with clinicopathological variables.Methods: A novel cluster analysis approach (Directed Cluster Analysis) was used to identify molecular biomarkers from genome-wide methylation array data. These novel DNA methylation biomarkers, together with previously identified CpG-site biomarkers and clinicopathological variables, were used to derive predictive classifiers for tumor progression.Results: The “triple classifier” which included both novel and previously identified DNA methylation biomarkers together with clinicopathological variables predicted tumor progression more accurately than the currently used Mayo scoring system, by increasing the specificity from 50% in Mayo to 64% in our triple classifier at 85% fixed sensitivity. The cumulative incidence of progress (pCIP5yr) was 7.5% in low-risk vs 44.7% in high-risk in M0 patients classified by the triple classifier at diagnosis.Conclusions: The triple classifier panel that combines clinicopathological variables with genome-wide methylation data has the potential to improve specificity in prognosis prediction for patients with non-metastatic ccRCC.
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| 4. |
- Andersson-Evelönn, Emma, 1983-
(författare)
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DNA methylation as a prognostic marker in clear cell Renal Cell Carcinoma
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma worldwide. Metastatic ccRCC is correlated to poor prognosis whereas non-metastatic disease has a 5-year survival rate up to 90%. Due to increased accessibility to different types of diagnostic imaging the frequency of metastatic ccRCC at diagnosis has decreased since the beginning of the 21st century. This has led to an earlier detection of primary tumors before patients present symptoms. However, 20-30% of the non-metastatic patients at diagnosis will progress and metastasize within five years of primary nephrectomy. Identifying patients at high risk of tumor progression at an early stage after diagnosis is of importance to improve outcome and survival. Currently, in Sweden, the Mayo scoring system is used to divide tumors into low, intermediate or high risk for tumor progression.DNA methylation has been associated with tumor development and progression in different malignancies. In this thesis, Illumina Infinium HumanMeth27 BeadChip Arrays and Human Meth450K BeadChip Arrays have been used to evaluate the relationship between methylation and clinicopathological variables as well as ccRCC outcome in 45 and 115 patients.Our studies identified an association between higher level of promoter-associated DNA methylation and clinicopathological variables in ccRCC. There was a significant stepwise increase of average methylation from tumor-free tissue, via non-metastatic tumors to metastatic disease. Cluster analysis divided patients into two distinct groups that differed in average methylation levels, TNM stage, Fuhrman nuclear grade, tumor size, survival and tumor progression. We also presented two prognostic classifiers for non-metastatic tumors; the promoter methylation classifier (PMC) panel and the triple classifier. The PMC panel divided tumors depending on the methylation level, PMC low or PMC high, with significantly worse prognosis in the PMC high group. This data was verified in an independent, publically available cohort. The triple classifier was created using a combination of clinicopathological variables, previously identified CpGs biomarkers and a novel cluster analysis approach (Directed Cluster Analysis). The triple classifier had a higher specificity compared to the clinically used Mayo scoring system and predicted tumor progression with higher accuracy at a fixed sensitivity.The identification of two epigenetic classifiers that predicted outcome in non-metastatic ccRCC further establishes the role of DNA methylation as a prognostic marker. This knowledge can contribute to identification of patients with a high risk of tumor progression and can be of importance in the decision regarding adjuvant treatment post-nephrectomy.
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| 5. |
- Andersson Evelönn, Emma, 1983-, et al.
(författare)
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DNA methylation associates with survival in non-metastatic clear cell renal cell carcinoma
- 2019
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Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype among renal cancer and is associated with poor prognosis if metastasized. Up to one third of patients with local disease at diagnosis will develop metastasis after nephrectomy, and there is a need for new molecular markers to identify patients with high risk of tumor progression. In the present study, we performed genome-wide promoter DNA methylation analysis at diagnosis to identify DNA methylation profiles associated with risk for progress.Method: Diagnostic tissue samples from 115 ccRCC patients were analysed by Illumina HumanMethylation450K arrays and methylation status of 155,931 promoter associated CpGs were related to genetic aberrations, gene expression and clinicopathological parameters.Results: The ccRCC samples separated into two clusters (cluster A/B) based on genome-wide promoter methylation status. The samples in these clusters differed in tumor diameter (p < 0.001), TNM stage (p < 0.001), morphological grade (p < 0.001), and patients outcome (5 year cancer specific survival (pCSS5yr) p < 0.001 and cumulative incidence of progress (pCIP5yr) p < 0.001. An integrated genomic and epigenomic analysis in the ccRCCs, revealed significant correlations between the total number of genetic aberrations and total number of hypermethylated CpGs (R = 0.435, p < 0.001), and predicted mitotic age (R = 0.407, p < 0.001). We identified a promoter methylation classifier (PMC) panel consisting of 172 differently methylated CpGs accompanying progress of disease. Classifying non-metastatic patients using the PMC panel showed that PMC high tumors had a worse prognosis compared with the PMC low tumors (pCIP5yr 38% vs. 8%, p = 0.001), which was confirmed in non-metastatic ccRCCs in the publically available TCGA-KIRC dataset (pCIP5yr 39% vs. 16%, p < 0.001).Conclusion: DNA methylation analysis at diagnosis in ccRCC has the potential to improve outcome-prediction in non-metastatic patients at diagnosis.
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| 6. |
- Andersson Evelönn, Emma, 1983-, et al.
(författare)
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DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC)
- 2016
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Ingår i: Tumor Biology. - : Springer Science and Business Media LLC. - 1010-4283 .- 1423-0380. ; 37:8, s. 10219-10228
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic alterations in the methylome have been associated with tumor development and progression in renal cell carcinoma (RCC). In this study, 45 tumor samples, 12 tumor-free kidney cortex tissues, and 24 peripheral blood samples from patients with clear cell RCC (ccRCC) were analyzed by genome-wide promoter-directed methylation arrays and related to clinicopathological parameters. Unsupervised hierarchical clustering separated the tumors into two distinct methylation groups (clusters A and B), where cluster B had higher average methylation and increased number of hypermethylated CpG sites (CpGs). Furthermore, tumors in cluster B had, compared with cluster A, a larger tumor diameter (p = 0.033), a higher morphologic grade (p < 0.001), a higher tumor-node-metastasis (TNM) stage (p < 0.001), and a worse prognosis (p = 0.005). Higher TNM stage was correlated to an increase in average methylation level (p = 0.003) and number of hypermethylated CpGs (p = 0.003), whereas a number of hypomethylated CpGs were mainly unchanged. However, the predicted age of the tumors based on methylation profile did not correlate with TNM stage, morphological grade, or methylation cluster. Differently methylated (DM) genes (n = 840) in ccRCC samples compared with tumor-free kidney cortex samples were predominantly hypermethylated and a high proportion were identified as polycomb target genes. The DM genes were overrepresented by transcription factors, ligands, and receptors, indicating functional alterations of significance for ccRCC progression. To conclude, increased number of hypermethylated genes was associated with increased TNM stage of the tumors. DNA methylation classification of ccRCC tumor samples at diagnosis can serve as a clinically applicable prognostic marker in ccRCC.
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| 7. |
- Andersson, Ulrika, et al.
(författare)
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Telomere length, allergies and risk of Glioma
- 2017
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 19:S3, s. 23-23
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Tidskriftsartikel (refereegranskat)abstract
- Background: In glioma, a malignant brain tumour with poor prognosis, the etiology is largely unkown. Rare inherited syndromes, and high doses of ionising radiation are associated with increased risk of glioma. Common genetic variants have been associated with risk of glioma, and familial glioma have been associated with genetic variants in genes functionally important in telomere regulation (e.g. RTEL, TERT and POT1). The association between telomere length and risk of cancer is complex and seems to be tumour type dependent. Patients with asthma have significantly shorter telomeres than those of control subjects, and a protective effect has been observed with an inverse association with allergies and asthma and glioma risk. Methods: We investigated population based glioma case-control series (431 cases and 672 controls) from Sweden at diagnosis with a quantitative PCR method for relative leukocyte telomere length measured in blood confirming with direct measurement of the association between telomere length and risk of glioma. We also explored the relationship between, age, gender, allergies and asthma, as these are established factors associated both with telomere length and glioma.Results: Longer relative leukocyte telomere length was significantly associated with increased risk of glioma, adjusting for age and gender (OR=2.23, CI: 1.11–4.47). As expected, for patients with allergies there was a protective effect with an inverse association with glioma risk, adjusting for age and gender (OR=0.64, CI; 0.48–0.85). Nevertheless, when analysing specific types of allergy, eczema (OR=0.66, CI; 0.41–1.08) and water eyes (OR=0.52, CI; 0.31–0.88) appeared to be more protective against glioma, compared to asthma (OR=0.92, CI; 0.59–1.41), and respiratory symptoms (OR=1.14, CI; 0.71–1.84) which showed no protective effect against glioma. Additionally adjusting for allergies did not markedly change the OR between relative leukocyte telomere length and glioma risk, indicating that the protective effect having allergies seems not to be coupled to telomere length. Conclusions: The adverse association of longer telomere and risk of glioma displays the complexity in understanding the biological role of telomere length and risk of developing cancer.
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| 8. |
- Andersson, Ulrika, et al.
(författare)
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The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking
- 2019
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Ingår i: Cancer Causes and Control. - : Springer. - 0957-5243 .- 1573-7225. ; 30:2, s. 177-185
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Previous studies have suggested an association between relative leukocyte telomere length (rLTL) and glioma risk. This association may be influenced by several factors, including allergies, BMI, and smoking. Previous studies have shown that individuals with asthma and allergy have shortened relative telomere length, and decreased risk of glioma. Though, the details and the interplay between rLTL, asthma and allergies, and glioma molecular phenotype is largely unknown. Methods: rLTL was measured by qPCR in a Swedish population-based glioma case–control cohort (421 cases and 671 controls). rLTL was related to glioma risk and health parameters associated with asthma and allergy, as well as molecular events in glioma including IDH1 mutation, 1p/19q co-deletion, and EGFR amplification. Results: Longer rLTL was associated with increased risk of glioma (OR = 1.16; 95% CI 1.02–1.31). Similar to previous reports, there was an inverse association between allergy and glioma risk. Specific, allergy symptoms including watery eyes was most strongly associated with glioma risk. High body mass index (BMI) a year prior diagnosis was significantly protective against glioma in our population. Adjusting for allergy, asthma, BMI, and smoking did not markedly change the association between longer rLTL and glioma risk. rLTL among cases was not associated with IDH1 mutation, 1p/19q co-deletion, or EGFR amplification, after adjusting for age at diagnosis and sex. Conclusions: In this Swedish glioma case–control cohort, we identified that long rLTL increases the risk of glioma, an association not confounded by allergy, BMI, or smoking. This highlights the complex interplay of the immune system, rLTL and cancer risk.
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| 9. |
- Bensberg, Maike, 1993-
(författare)
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DNA methylation in T cell leukaemia
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- T cell acute lymphoblastic leukaemia (T-ALL) is a predominantly paediatric cancer that stems from malignant transformation of developing T cells. While the disease has an overall survival rate of 80%, the intense chemotherapy treatment causes severe toxicity and long-term side effects. Furthermore, the survival rate for patients in relapse is less than 25%. Consequently, there is a need for improved therapy options to reduce treatment-related side effects and improve the survival rate of relapsed patients. Targeting aberrant DNA methylation with hypomethylating agents (HMAs) has been successful in the treatment of myelodysplastic syndromes and acute myeloid leukaemia but has not been routinely used in the treatment of T-ALL, despite DNA hypomethylation being observed in T-ALL patients. In this work, we employed a comprehensive set of molecular and sequencing-based techniques to explore the possibilities of HMAs as a treatment option for T-ALL.We made the discovery that the DNA demethylating enzyme ten-eleven translocation 2, TET2, is downregulated or completely silenced in primary T-ALL. Moreover, the TET2 promoter was highly methylated in a group of patients, suggesting that TET2 itself can be silenced through DNA methylation in T-ALL. By treatment with HMAs, TET2 was demethylated in T-ALL cell lines and was one of few genes that was activated upon loss of DNA methylation, indicating that TET2 expression is regulated by DNA methylation in T-ALL cell lines. The development of a novel HMA, the DNMT1-specific inhibitor GSK-3685032, offers a tool to reveal the mechanism of action of the traditional HMAs, 5- azacytidine and decitabine, and to study the effects of acute loss of DNA methylation on cancer cells. We found that 5-azacytidine and decitabine are cytotoxic to T-ALL cells primarily by creating DNA double strand breaks. In contrast, GSK did not prompt a DNA damage response and instead reduced global DNA methylation to as little as 18% with limited cytotoxicity only occurring after levels of DNA methylation had dropped below 30%, a level of demethylation not achieved with DEC or AZA.T-ALL is more than two times more common in boys than girls and mutations in X-linked tumour suppressor genes that escape X inactivation, have been suggested as an underlying cause for the observed sex-bias. In theory, these aberrations would be more detrimental in XYmale cells than in XX-female cells due to the presence of an extra protective copy of the gene in females. We profiled DNA methylation during T cell development and created a map of sex-specific gene expression and expression from the inactive X chromosome, finding that some, but not all, suggested tumour suppressor genes in fact escape X inactivation. These results highlight the importance of profiling the healthy cells that T-ALL arises from to correctly judge the functional impact of gene dysregulation in cancer.In the last study, we aimed to investigate the role of N6-adenine methylation (6mdA) during T cell differentiation. While 6mdA is common in bacteria it is much rarer in humans. Nevertheless, 6mdA has previously been associated with several cellular processes, including cancer progression. Our study calls the presence of 6mdA in mammals into question by exposing limitations of the techniques used in its analysis. We show that contamination with bacterial DNA or 6mAcontaining RNA, nonspecific antibody binding, and low precision of third-generation sequencing techniques all hinder the detection and investigation of rare DNA modifications, such as 6mdA.Together, this work is an in-depth study of the function and the potential of DNA methylation in the biology of healthy and malignant T cells.
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| 10. |
- Borssén, Magnus, et al.
(författare)
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DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia
- 2016
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 63:7, s. 1185-1192
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Tidskriftsartikel (refereegranskat)abstract
- Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.
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