| 21. |
- Falck, Anna-Karin, et al.
(författare)
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St Gallen molecular subtypes in screening-detected and symptomatic breast cancer in a prospective cohort with long-term follow-up.
- 2016
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 103:5, s. 513-523
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Tidskriftsartikel (refereegranskat)abstract
- Diagnosis by screening mammography is considered an independent positive prognostic factor, although the data are not fully in agreement. The aim of the study was to explore whether the mode of detection (screening-detected versus symptomatic) adds prognostic information to the St Gallen molecular subtypes of primary breast cancer, in terms of 10-year cumulative breast cancer mortality (BCM).
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| 22. |
- Hörnquist, Lina, et al.
(författare)
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Altered self-perception in adult survivors treated for a CNS tumor in childhood or adolescence : population-based outcomes compared with the general population
- 2015
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Ingår i: Neuro-Oncology. - : Oxford University Press (OUP). - 1522-8517 .- 1523-5866. ; 17:5, s. 733-40
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Survivors of pediatric CNS tumors are at risk for persistent tumor/treatment-related morbidity, physical disability and social consequences that may alter self-perception, vital for self-identity, mental health and quality of survival. We studied the long-term impact of childhood CNS tumors and their treatment on the self-perception of adult survivors and compared outcomes with those of the general population.METHODS: The cohort included 697 Swedish survivors diagnosed with a primary CNS tumor during 1982-2001. Comparison data were randomly collected from a stratified general population sample. Survivors and general population individuals were compared as regards self-perception in 5 domains: body image, sports/physical activities, peers, work, and family, and with a global self-esteem index. Within the survivor group, determinants of impact on self-perception were identified.RESULTS: The final analyzed sample included 528 survivors, 75.8% of the entire national cohort. The control sample consisted of 995, 41% of 2500 addressed. Survivors had significantly poorer self-perception outcomes in domains of peers, work, body image, and sports/physical activities, and in the global self-perception measure, compared with those of the general population (all P < .001). Within the survivor group, female gender and persistent visible physical sequelae predicted poorer outcomes in several of the studied domains. Tumor type and a history of cranial radiation therapy were associated with outcomes.CONCLUSION: An altered self-perception is a potential late effect in adult survivors of pediatric CNS tumors. Self-perception and self-esteem are significant elements of identity, mental health and quality of survival. Therefore, care and psychosocial follow-up of survivors should include measures for identifying disturbances and for assessing the need for psychosocial intervention.
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| 23. |
- Jakobsen Falk, Ingrid, et al.
(författare)
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TP53 mutations and MDM2(SNP309) identify subgroups of AML patients with impaired outcome
- 2015
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 94:4, s. 355-362
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundTP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of mouse double minute 2 (MDM2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. Experimental designWe investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2(SNP309) on treatment outcome and overall survival (OS) in 189 Swedish acute myeloid leukemia patients. The genetic analyses were performed using SSCA and direct sequencing (for mutations in exon 5-8 of TP53) and Pyrosequencing (for the MDM2(SNP309)). ResultsWe found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with association to high-risk cytogenetics (P<0.001). TP53mut patients had lower response rates (22% compared with 76% CR in TP53 wild-type (wt) patients, P<0.001) and reduced OS (2 and 16months, respectively, P<0.001). In TP53wt patients with high or intermediate risk cytogenetic aberrations, the MDM2(SNP309) conferred an impaired outcome, with patients carrying the alternative G-allele having shorter OS compared with T/T patients (median 9 vs. 50months, P=0.020). ConclusionsOur results show that TP53mut analysis and MDM2(SNP309) genotyping may be useful tools for prognostication, risk stratification, and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.
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| 24. |
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| 25. |
- Juul-Dam, KL, et al.
(författare)
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Patient-Tailored Deep Sequencing of Peripheral Blood Enables Early Detection of Relapse in Childhood Acute Myeloid Leukemia
- 2019
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Ingår i: Blood Vpl 134 Suppl 1 1456. - : American Society of Hematology. - 0006-4971 .- 1528-0020.
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Konferensbidrag (refereegranskat)abstract
- Relapse remains a major therapeutic challenge in children with acute myeloid leukemia (AML). Outcome after relapse may improve if preemptive therapy is initiated at first evidence of leukemia regrowth. Early detection of imminent relapse requires molecular measurable residual disease (MRD) monitoring after therapy completion. Today, this is possible only in about 40% of children with AML that harbor genetic abnormalities applicable for quantification using standardized qPCR assays. To enable disease surveillance for all patients, we developed patient-tailored deep sequencing (DS) MRD analysis, which provides highly sensitive detection of leukemia-specific mutations. We investigated the potential of this method for early relapse detection in peripheral blood (PB), the only easily accessible source for MRD sampling in children. PB samples were collected at monthly intervals during follow-up from 45 children diagnosed with AML and treated according to The Nordic Society of Pediatric Haematology and Oncology (NOPHO)-DBH AML 2012 protocol between January 2013 and May 2016 in Denmark, Norway, Sweden and Finland (508 samples, median 11 samples/patient, range 3-27). Nine patients with relapse (median age 5 years, range 0-8) had available diagnostic and relapse material and were included in this study. The patients displayed core binding factor abnormalities (n=3), KMT2A-rearrangements (n=3), monosomy 7 (n=1) or normal karyotype (n=2) at AML diagnosis. Leukemia-specific single nucleotide variants (SNVs) were identified with exome sequencing (ES) of sorted leukemic cells with lymphocytes or remission PB as constitutive DNA template. A variant allele frequency (VAF) with 95% confidence interval including 50% indicates presence of the mutation in all leukemic cells at diagnosis. With the exception of 2 cases with only subclonal mutations at diagnosis, leukemia-specific SNVs with VAF of 50% at diagnosis and persistence at relapse were selected as MRD targets. MRD target mutations were quantified in PB samples preceding overt relapse using patient-tailored DS assays with sensitivity of VAF 0.02%. In diagnostic samples, ES identified 53 leukemia-specific SNVs (median 4 SNVs/patient, range 2-12) of which 33 were also present at relapse (median 2 SNVs/patient, range 1-9). The number of mutations identified at diagnosis increased with age (Rs 0.83, p=0.006). All patients had at least one leukemia-specific SNV detected at both diagnosis and relapse. Twenty-one MRD target mutations (median 2 SNVs/patient, range 1-3) were quantified in PB (55 samples, median sampling interval 28 days, range 11-80) using DS. In 8/9 patients, at least one SNV was detected in PB before overt relapse occurred. The first PB sample showing MRD positivity (median VAF 0.14%, range 0.03-0.44) preceded hematological relapse at a median interval of 3 months (range 0-7.9). In 6 patients not preemptively treated, the median doubling time based on VAF increments was 7 days, with great variability between individuals and genotypes (range 4-28 days). Three patients had molecular relapse diagnosed by qPCR used in clinical diagnostics and received individualized preemptive treatment. In these 3 patients, DS detected mutations in PB for >100 days preceding overt relapse and the doubling times were 14, 25 and 36 days. In conclusion, DS of leukemia-specific mutations at frequent intervals in PB enables early detection of relapse and ES at diagnosis may identify SNVs applicable for such longitudinal MRD monitoring. This approach facilitates molecular disease surveillance and initiation of preemptive therapy in AML patients without established qPCR targets.
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| 26. |
- Karrman, Kristina, et al.
(författare)
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Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia reveal NOTCH1 mutations in minor subclones and a high incidence of uniparental isodisomies affecting CDKN2A
- 2015
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Ingår i: Journal of Hematology & Oncology. - : Springer Science and Business Media LLC. - 1756-8722. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that arises in a multistep fashion through acquisition of several genetic aberrations, subsequently giving rise to a malignant, clonal expansion of T-lymphoblasts. The aim of the present study was to identify additional as well as cooperative genetic events in T-ALL.Methods: A population-based pediatric T-ALL series comprising 47 cases was investigated by SNP array and deep sequencing analyses of 75 genes, in order to ascertain pathogenetically pertinent aberrations and to identify cooperative events.Results: The majority (92%) of cases harbored copy number aberrations/uniparental isodisomies (UPIDs), with a median of three changes (range 0-11) per case. The genes recurrently deleted comprised CDKN2A, CDKN2B, LEF1, PTEN, RBI, and STIL. No case had a whole chromosome UPID; in fact, literature data show that this is a rare phenomenon in T-ALL. However, segmental UPIDs (sUPIDs) were seen in 42% of our cases, with most being sUPID9p that always were associated with homozygous CDKN2A deletions, with a heterozygous deletion occurring prior to the sUPID9p in all instances. Among the 75 genes sequenced, 14 (19%) were mutated in 28 (72%) of 39 analyzed cases. The genes targeted are involved in signaling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse; thus, such mutations can be secondary events.Conclusions: Deep sequencing and SNP array analyses of T-ALL revealed lack of wUPIDs, a high proportion of sUPID9p targeting CDKN2A, NOTCH1 mutations in subclones, and recurrent mutations of genes involved in signaling transduction, epigenetic regulation, and transcription.
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| 27. |
- Kopparapu, Pradeep Kumar, et al.
(författare)
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Epigenetic silencing of miR-26A1 in chronic lymphocytic leukemia and mantle cell lymphoma: Impact on EZH2 expression. : Epigenetic inactivation of miR - 26A1 in CLL and MCL
- 2016
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 11:5, s. 335-343
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Tidskriftsartikel (refereegranskat)abstract
- Downregulation of miR26A1 has been reported in various B-cell malignancies; however, the mechanism behind its deregulation remains largely unknown. We investigated miR26A1 methylation and expression levels in a well-characterized series of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). From 450K methylation arrays, we first observed miR26A1 (cg26054057) as uniformly hypermethylated in MCL (n=24) (all >75%), while CLL (n=18) showed differential methylation between prognostic subgroups. Extended analysis using pyrosequencing confirmed our findings and real-time quantitative PCR verified low miR26A1 expression in both CLL (n=70) and MCL (n=38) compared to normal B-cells. Notably, the level of miR26A1 methylation predicted outcome in CLL, with higher levels seen in poor-prognostic, IGHV-unmutated CLL. Since EZH2 was recently reported as a target for miR26A1, we analyzed the expression levels of both miR26A1 and EZH2 in primary CLL samples and observed an inverse correlation. By overexpression of miR26A1 in CLL and MCL cell lines, reduced EZH2 protein levels were observed using both Western blot and flow cytometry. In contrast, methyl-inhibitor treatment led to upregulated miR26A1 expression with a parallel decrease of EZH2 expression. Finally, increased levels of apoptosis were observed in miR26A1-overexpressing cell lines, further underscoring the functional relevance of miR26A1. In summary, we propose that epigenetic silencing of miR26A1 is required for the maintenance of increased levels of EZH2, which in turn translate into a worse outcome, as shown in CLL, highlighting miR26A1 as a tumor suppressor miRNA.
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| 28. |
- Lee, SangWook, et al.
(författare)
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Network analyses identify liver-specific targets for treating liver diseases
- 2017
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Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- We performed integrative network analyses to identify targets that can be used for effectively treating liver diseases with minimal side effects. We first generated co-expression networks (CNs) for 46 human tissues and liver cancer to explore the functional relationships between genes and examined the overlap between functional and physical interactions. Since increased de novo lipogenesis is a characteristic of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC), we investigated the liver-specific genes co-expressed with fatty acid synthase (FASN). CN analyses predicted that inhibition of these liver-specific genes decreases FASN expression. Experiments in human cancer cell lines, mouse liver samples, and primary human hepatocytes validated our predictions by demonstrating functional relationships between these liver genes, and showing that their inhibition decreases cell growth and liver fat content. In conclusion, we identified liver-specific genes linked to NAFLD pathogenesis, such as pyruvate kinase liver and red blood cell (PKLR), or to HCC pathogenesis, such as PKLR, patatin-like phospholipase domain containing 3 (PNPLA3), and proprotein convertase subtilisin/kexin type 9 (PCSK9), all of which are potential targets for drug development.
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| 29. |
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| 30. |
- Sandén, Emma, et al.
(författare)
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Preoperative systemic levels of VEGFA, IL-7, IL-17A, and TNF-beta delineate two distinct groups of children with brain tumors
- 2016
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Ingår i: Pediatr Blood Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 63:12, s. 2112-2122
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPrimary brain tumors are the most common solid tumors in children. Increasing evidence demonstrates diverse intratumoral immune signatures, which are tentatively reflected in peripheral blood. ProcedureTwenty cytokines were analyzed in preoperative plasma samples from five healthy children and 45 children with brain tumors, using a multiplex platform (MesoScale Discovery V-PLEX (R)). Tumor types included medulloblastoma (MB), ependymoma, sarcoma, high-grade glioma, pilocytic astrocytoma, and other low-grade gliomas. ResultsA panel of four cytokines [VEGFA, interleukin (IL)-7, IL-17A, and tumor necrosis factor (TNF)-] delineated two distinct patient groups, identified as VEGFA(high)IL-7(high)IL-17A(low)TNF-(low) (Group A) and VEGFA(low)IL-7(low)IL-17A(high)TNF-(high) (Group B). Healthy controls and the vast majority of patients with MB were found within Group A, whereas patients with other tumor types were equally distributed between the two groups. Unrelated to A/B affiliation, we detected trends toward increased IL-10 and decreased IL-12/23 and TNF- in several tumor types. Finally, a small number of patients displayed evidence of enhanced systemic immune activation, including elevated levels of interferon-, granulocyte monocyte colony-stimulating factor, IL-6, IL-12/23, and TNF-. Following tumor resection, cytokine levels in a MB patient approached the levels of healthy controls. ConclusionsWe identify common features and individual differences in the systemic immune profiles of children with brain tumors. Overall, patients with MB displayed a uniform cytokine profile, whereas other tumor diagnoses did not predict systemic immunological status in single patients. Future characterization and monitoring of systemic immune responses in children with brain tumors will have important implications for the development and implementation of immunotherapy.
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