| 1. |
- Försti, Asta, et al.
(författare)
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Polymorphisms in the transforming growth factor beta 1 pathway in relation to colorectal cancer progression
- 2010
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Ingår i: Genes, Chromosomes and Cancer. - New York : Liss. - 1045-2257 .- 1098-2264. ; 49:3, s. 270-281
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Tidskriftsartikel (refereegranskat)abstract
- Transforming growth factor beta1 (TGFB1) acts as a growth inhibitor of normal colonic epithelial cells, however, as a tumor promoter of colorectal cancer (CRC) cells. To explore the association between genetic polymorphisms in the TGFB1 pathway and CRC susceptibility and clinical outcome, we carried out a case-control study on a Swedish population of 308 CRC cases and 585 age- and gender-matched controls. The cases were sampled prospectively and had up to 16 years follow-up, making the study material particularly suitable for survival analysis. On the basis of their reported or predicted functional effect, nine single-nucleotide polymorphisms (TGFB1: Leu10Pro; TGFBR1: 9A/6A and IVS7G+24A; FURIN: C-229T; THBS1: T+42C; LTBP1L: C-256G; LTBP4: T-893G and Thr750Ala; BAMBI: T-779A) were selected for genotyping. We evaluated the associations between genotypes and CRC and Dukes' stage. Survival probabilities were compared between different subgroups. The observed statistically significant associations included a decreased CRC risk for TGFBR1 IVS7G+24A minor allele carriers (odds ratio (OR): 0.72, 95% confidence interval (CI): 0.53-0.97), less aggressive tumors with Dukes' stage A+B for carriers of LTBP4 Thr750Ala and BAMBI T-779A minor alleles (OR: 0.58, 95%CI: 0.36-0.93 and OR: 0.51, 95%CI: 0.29-0.89, respectively) and worse survival for FURIN C-229T heterozygotes (hazard ratio: 1.63, 95%CI: 1.08-2.46). As this is the first study about the influence of the polymorphisms in the TGFB1 pathway on CRC progression, further studies in large independent cohorts are warranted.
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| 2. |
- Biloglav, Andrea, et al.
(författare)
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SFPQ-ABL1-positive B-cell precursor acute lymphoblastic leukemias
- 2020
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264.
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, a subgroup of B‐cell precursor acute lymphoblastic leukemia (BCP ALL) without an established abnormality (“B‐other”) has been shown to be characterized by rearrangements of ABL1 , ABL2 , CSF1R , or PDGFRB (a.k.a. ABL‐class genes). Using FISH with probes for these genes, we screened 55 pediatric and 50 adult B‐other cases. Three (6%) of the adult but none of the childhood B‐other cases were positive for ABL‐class aberrations. RT‐PCR and sequencing confirmed a rare SFPQ‐ABL1 fusion in one adult B‐other case with t(1;9)(p34;q34). Only six SFPQ ‐ABL1 ‐positive BCP ALLs have been reported, present case included. A review of these shows that all harbored fusions between exon 9 of SFPQ and exon 4 of ABL1 , that the fusion is typically found in adolescents/younger adults without hyperleukocytosis, and that IKZF1 deletions are recurrent. The few patients not treated with tyrosine kinase inhibitors (TKIs) and/or allogeneic stem cell transplantation relapsed, strengthening the notion that TKI should be added to the therapy of SFPQ ‐ABL1 ‐positive BCP ALL.
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| 3. |
- Cabrerizo Granados, David, et al.
(författare)
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The clinical phenotype of germline RUNX1 mutations in relation to the accompanying somatic variants and RUNX1 isoform expression
- 2023
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Ingår i: Genes, Chromosomes and Cancer. - : John Wiley & Sons. - 1045-2257 .- 1098-2264. ; 62:11, s. 672-677
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Tidskriftsartikel (refereegranskat)abstract
- Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, abnormal bleeding, and an elevated risk of developing myelodysplastic neoplasia (MDS) and acute myeloid leukemia (AML) at young age. However, it is not known why or how germline carriers of RUNX1 mutations have a particular propensity to develop myeloid hematologic malignancies, but the acquisition and composition of somatic mutations are believed to initiate and determine disease progression. We present a novel family pedigree that shares a common germline RUNX1R204* variant and exhibits a spectrum of somatic mutations and related myeloid malignancies (MM). RUNX1 mutations are associated with inferior clinical outcome; however, the proband of this family developed MDS with ring sideroblasts (MDS-RS), classified as a low-risk MDS subgroup. His relatively indolent clinical course is likely due to a specific somatic mutation in the SF3B1 gene. While the three main RUNX1 isoforms have been ascribed various roles in normal hematopoiesis, they are now being increasingly recognized as involved in myeloid disease. We investigated the RUNX1 transcript isoform patterns in the proband and his sister, who carries the same germline RUNX1R204* variant, and has FPDMM but no MM. We demonstrate a RUNX1a increase in MDS-RS, as previously reported in MM. Interestingly, we identify a striking unbalance of RUNX1b and -c in FPDMM. In conclusion, this report reinforces the relevance of somatic variants on the clinical phenotypic heterogeneity in families with germline RUNX1 deficiency and investigates a potential new role for RUNX1 isoform disequilibrium as a mechanism for development of MM.
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| 4. |
- Fehr, Andre, et al.
(författare)
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Increased MYB alternative promoter usage is associated with relapse in acute lymphoblastic leukemia
- 2023
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Ingår i: Genes Chromosomes & Cancer. - : John Wiley & Sons. - 1045-2257 .- 1098-2264. ; 62:10, s. 597-606
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Tidskriftsartikel (refereegranskat)abstract
- Therapy-resistant disease is a major cause of death in patients with acute lympho-blastic leukemia (ALL). Activation of the MYB oncogene is associated with ALL and leads to uncontrolled neoplastic cell proliferation and blocked differentiation. Here, we used RNA-seq to study the clinical significance of MYB expression and MYB alter-native promoter (TSS2) usage in 133 pediatric ALLs. RNA-seq revealed that all cases analyzed overexpressed MYB and demonstrated MYB TSS2 activity. qPCR analyses confirmed the expression of the alternative MYB promoter also in seven ALL cell lines. Notably, high MYB TSS2 activity was significantly associated with relapse (p = 0.007). Moreover, cases with high MYB TSS2 usage showed evidence of therapy-resistant disease with increased expression of ABC multidrug resistance transporter genes (e.g., ABCA2, ABCB5, and ABCC10) and enzymes catalyzing drug degradation (e.g., CYP1A2, CYP2C9, and CYP3A5). Elevated MYB TSS2 activity was further associated with augmented KRAS signaling (p < 0.05) and decreased methyla-tion of the conventional MYB promoter (p < 0.01). Taken together, our results sug-gest that MYB alternative promoter usage is a novel potential prognostic biomarker for relapse and therapy resistance in pediatric ALL.
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| 5. |
- Fransson, Susanne, 1975, et al.
(författare)
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Intragenic anaplastic lymphoma kinase (ALK) rearrangements: Translocations as a novel mechanism of ALK activation in neuroblastoma tumors.
- 2015
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 54:2, s. 99-109
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Tidskriftsartikel (refereegranskat)abstract
- Anaplastic lymphoma kinase (ALK) has been demonstrated to be deregulated in sporadic as well as in familiar cases of neuroblastoma (NB). Whereas ALK-fusion proteins are common in lymphoma and lung cancer, there are few reports of ALK rearrangements in NB indicating that ALK mainly exerts its oncogenic capacity via activating mutations and/or overexpression in this tumor type. In this study, 332 NB tumors and 13 cell lines were screened by high resolution single nucleotide polymorphism microarray. Gain of 2p was detected in 23% (60/332) of primary tumors and 46% (6/13) of cell lines, while breakpoints at the ALK locus were detected in four primary tumors and two cell lines. These were further analyzed by next generation sequencing and a targeted enrichment approach. Samples with both ALK and MYCN amplification displayed complex genomic rearrangements with multiple breakpoints within the amplicon. None of the translocations characterized in primary NB tumors are likely to result in a chimeric protein. However, immunohistochemical analysis reveals high levels of phosphorylated ALK in these samples despite lack of initial exons, possibly due to alternative transcription initiation sites. Both ALK proteins predicted to arise from such alterations and from the abnormal ALK exon 4-11 deletion observed in the CLB-BAR cell line show strong activation of downstream targets STAT3 and extracellular signal-regulated kinase (ERK) when expressed in PC12 cells. Taken together, our data indicate a novel, although rare, mechanism of ALK activation with implications for NB tumorigenesis.
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| 6. |
- Höiom, Veronica, et al.
(författare)
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Hereditary uveal melanoma : A report of a germline mutation in BAP1
- 2013
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 52:4, s. 378-384
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Tidskriftsartikel (refereegranskat)abstract
- Melanoma of the eye is a rare and distinct subtype of melanoma, which only rarely are familial. However, cases of uveal melanoma (UM) have been found in families with mixed cancer syndromes. Here, we describe a comprehensive search for inherited genetic variation in a family with multiple cases of UM but no aggregation of other cancer diagnoses. The proband is a woman diagnosed with UM at 16 years who within 6 months developed liver metastases. We also identified two older paternal relatives of the proband who had died from UM. We performed exome sequencing of germline DNA from members of the affected family. Exome-wide analysis identified a novel loss-of-function mutation in the BAP1 gene, previously suggested as a tumor suppressor. The mutation segregated with the UM phenotype in this family, and we detected a loss of the wild-type allele in the UM tumor of the proband, strongly supporting a causative association with UM. Screening of BAP1 germline mutations in families predisposed for UM may be used to identify individuals at increased risk of disease. Such individuals may then be enrolled in preventive programs and regular screenings to facilitate early detection and thereby improve prognosis.
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| 7. |
- Laursen, Anne Cathrine Lund, et al.
(författare)
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Trisomy 8 in pediatric acute myeloid leukemia : A NOPHO-AML study
- 2016
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 55:9, s. 719-726
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Tidskriftsartikel (refereegranskat)abstract
- Trisomy 8 (+8) is a common cytogenetic aberration in acute myeloid leukemia (AML); however, the impact of +8 in pediatric AML is largely unknown. We retrospectively investigated 609 patients from the NOPHO-AML database to determine the clinical and cytogenetic characteristics of +8 in pediatric AML and to investigate its prognostic impact. Complete cytogenetic data were available in 596 patients (98%) aged 0-18 years, diagnosed from 1993 to 2012, and treated according to the NOPHO-AML 1993 and 2004 protocols in the Nordic countries and Hong Kong. We identified 86 patients (14%) with +8. Trisomy 8 was combined with other cytogenetic aberrations in 68 patients (11%) (+8 other) and in 18 patients (3%), it was the sole abnormality (+8 alone). Trisomy 8 was associated with FAB M5 (36%) but otherwise clinically comparable with non-trisomy 8 patients. Trisomy 8 was favorable in patients of young age and with t(9;11). Trisomy 8 alone was associated with older age (median age 10.1 years), FAB M2 (33%), and FLT3-ITD mutations (58%). The 5-year event-free survival for patients with +8 alone was 50% and 5-year overall survival was 75%. In conclusion, +8 is one of the most common cytogenetic aberrations in pediatric AML. Trisomy 8 positive AML is a heterogeneous group and the majority of cases have additional cytogenetic aberrations. Patients with +8 alone differed from patients with +8 other and were associated with older age, FAB M2, and FLT3-ITD aberrations. There were no differences in survival despite the more frequent occurrence of FLT3-ITD in +8 alone.
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| 8. |
- Li, Huiqi, et al.
(författare)
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Telomere length and LINE1 methylation is associated with chromosomal aberrations in peripheral blood.
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264.
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Tidskriftsartikel (refereegranskat)abstract
- The frequency of chromosomal aberrations in peripheral blood predicts a probable cancer risk. The individual telomere length and methylation of repetitive elements may be susceptibility factors for chromosomal aberrations. A cohort of healthy Norwegian men (N = 364) recruited during 1980-1999 were analyzed for chromosomal aberrations in phytohemagglutinin-stimulated lymphocytes from peripheral blood. Chromosome-type or chromatid-type aberrations were scored. DNA was extracted from slides cytogenetically analyzed and relative average telomere length and methylation of LINE1 repeats were determined by quantitative polymerase chain reaction and bisulfite pyrosequencing, respectively. Information about individuals with malignant tumors (N = 49) diagnosed after chromosomal aberrations testing until end of 2008 was obtained and two matched controls per case were used in a nested case-control analysis. Shorter relative telomere length and higher methylation of LINE1 were associated with higher frequency of total chromosomal aberrations (β = -0.76, P = 0.022; and β = 0.042, P = 0.048, respectively; age-adjusted ordinal regression). The telomere length was stronger associated with chromosome-type (β = -1.00, P = 0.006) than with chromatid-type aberrations (β = -0.49, P = 0.115). The LINE1 methylation was stronger associated with chromatid-type (β = 0.062, P = 0.003) than with chromosome-type aberrations (β = 0.018, P = 0.41). Telomere length [individuals with short telomeres odds ratio (OR) = 0.87, 95% confidence interval (CI) 0.38-2.0], LINE1 (individuals with high methylation OR = 1.04, 95% CI 0.43-2.5) and chromosomal aberrations (individuals with high frequency OR = 1.6, 95% CI 0.63-3.9) at baseline did not predict cancer risk, but the conclusions were hampered by low statistical precision. The results suggest that shorter telomere length and higher LINE1 methylation in peripheral blood lymphocytes are predisposition factors for increased frequency of chromosomal aberrations. © 2012 Wiley Periodicals, Inc.
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| 9. |
- Lundin, Catarina, et al.
(författare)
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High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - Malden : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 51:2, s. 196-206
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Tidskriftsartikel (refereegranskat)abstract
- Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as less than10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrentdup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.
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| 10. |
- Orsmark-Pietras, Christina, et al.
(författare)
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Clinical and genomic characterization of patients diagnosed with the provisional entity acute myeloid leukemia with BCR-ABL1, a Swedish population-based study
- 2021
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley-Liss Inc.. - 1045-2257 .- 1098-2264. ; 60:6, s. 426-433
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) with t(9;22)(q34;q11), also known as AML with BCR-ABL1, is a rare, provisional entity in the WHO 2016 classification and is considered a high-risk disease according to the European LeukemiaNet 2017 risk stratification. We here present a retrospective, population-based study of this disease entity from the Swedish Acute Leukemia Registry. By strict clinical inclusion criteria we aimed to identify genetic markers further distinguishing AML with t(9;22) as a separate entity. Twenty-five patients were identified and next-generation sequencing using a 54-gene panel was performed in 21 cases. Interestingly, no mutations were found in NPM1, FLT3, or DNMT3A, three frequently mutated genes in AML. Instead, RUNX1 was the most commonly mutated gene, with aberrations present in 38% of the cases compared to around 10% in de novo AML. Additional mutations were identified in genes involved in RNA splicing (SRSF2, SF3B1) and chromatin regulation (ASXL1, STAG2, BCOR, BCORL1). Less frequently, mutations were found in IDH2, NRAS, TET2, and TP53. The mutational landscape exhibited a similar pattern as recently described in patients with chronic myeloid leukemia (CML) in myeloid blast crisis (BC). Despite the concomitant presence of BCR-ABL1 and RUNX1 mutations in our cohort, both features of high-risk AML, the RUNX1-mutated cases showed a superior overall survival compared to RUNX1 wildtype cases. Our results suggest that the molecular characteristics of AML with t(9;22)/BCR-ABL1 and CML in myeloid BC are similar and do not support a distinction of the two disease entities based on their underlying molecular alterations.
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