| 1. |
- Afshari, Maryam K., et al.
(författare)
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Activation of PLAG1 and HMGA2 by gene fusions involving the transcriptional regulator gene NFIB
- 2020
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Ingår i: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 59:11, s. 652-660
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Tidskriftsartikel (refereegranskat)abstract
- The pleomorphic adenoma (PA), which is the most common salivary gland neoplasm, is a benign tumor characterized by recurrent chromosome rearrangements involving 8q12 and 12q14-15. We have previously shown that thePLAG1andHMGA2oncogenes are the targets of these rearrangements. Here, we have identified previously unrecognized subsets of PAs with ins(9;8)/t(8;9) (n = 5) and ins(9;12)/t(9;12) (n = 8) and breakpoints located in the vicinity of thePLAG1andHMGA2loci. RNA-sequencing and reverse transcriptase (RT)-PCR analyses of a case with an ins(9;8) revealed a novelNFIB-PLAG1fusion in whichNFIBexon 4 is linked toPLAG1exon 3. In contrast to the developmentally regulatedPLAG1gene,NFIBwas highly expressed in normal salivary gland, indicating thatPLAG1in this case, as in other variant fusions, is activated by promoter swapping. RT-PCR analysis of three PAs with t(9;12) revealed two tumors with chimeric transcripts consisting ofHMGA2exon 4 linked toNFIBexons 9 or 3 and one case with a fusion linkingHMGA2exon 3 toNFIBexon 9. TheNFIBfusion events resulted in potent activation ofPLAG1andHMGA2. Analysis of the chromatin landscape surroundingNFIBrevealed several super-enhancers in the 5 '- and 3 '-parts of theNFIBlocus and its flanking sequences. These findings indicate thatPLAG1andHMGA2, similar toMYBin adenoid cystic carcinoma, may be activated by enhancer-hijacking events, in which super-enhancers inNFIBare translocated upstream ofPLAG1or downstream ofHMGA2. Our results further emphasize the role ofNFIBas a fusion partner to multiple oncogenes in histopathologically different types of salivary gland tumors.
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| 2. |
- Andersson, Natalie, et al.
(författare)
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Inactivation of RB1, CDKN2A and TP53 have distinct effects on genomic stability at side-by-side comparison in karyotypically normal cells
- 2023
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 62:2, s. 93-100
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Tidskriftsartikel (refereegranskat)abstract
- Chromosomal instability is a common feature in malignant tumors. Previous studies have indicated that inactivation of the classical tumor suppressor genes RB1, CDKN2A and TP53 may contribute to chromosomal aberrations in cancer by disrupting different aspects of the cell cycle and DNA damage checkpoint machinery. We performed a side-by-side comparison of how inactivation of each of these genes affected chromosomal stability in vitro. Using CRISPR-Cas9 technology, RB1, CDKN2A and TP53 were independently knocked out in karyotypically normal immortalized cells, after which these cells were followed over time. Bulk RNA sequencing revealed a distinct phenotype with upregulation of pathways related to cell cycle control and proliferation in all three knockouts. Surprisingly, the RB1 and CDKN2A knocked out cell lines did not harbor more copy number aberrations than wild-type cells, despite culturing for months. The TP53-knocked out cells, in contrast, showed a massive amount of copy number alterations and saltatory evolution through whole genome duplication. This side-by-side comparison indicated that the effects on chromosomal stability from inactivation of RB1 and CDKN2A are negligible compared to inactivation of TP53, under the same conditions in a non-stressful environment, even though partly overlapping regulatory pathways are affected.
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| 3. |
- Arbajian, Elsa, et al.
(författare)
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Deep sequencing of myxoinflammatory fibroblastic sarcoma
- 2020
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 59:5, s. 309-317
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Tidskriftsartikel (refereegranskat)abstract
- Myxoinflammatory fibroblastic sarcoma (MIFS) has recurrent genetic features in the form of a translocation t(1;10)(p22-31;q24-25), BRAF gene fusions, and/or an amplicon in 3p11-12 including the VGLL3 gene. The breakpoints on chromosomes 1 and 10 in the t(1;10) cluster in or near the TGFBR3 and OGA genes, respectively. We here used a combination of deep sequencing of the genome (WGS), captured sequences (Cap-seq), and transcriptome (RNA-seq) and genomic arrays to investigate the molecular outcome of the t(1;10) and the VGLL3 amplicon, as well as to assess the spectrum of other recurrent genomic features in MIFS. Apart from a ROBO1-BRAF chimera in a t(1;10)-negative MIFS-like tumor, no fusion gene was found at RNA-seq. This was in line with WGS and Cap-seq results, revealing variable breakpoints in chromosomes 1 and 10 and genomic breakpoints that should not yield functional fusion transcripts. The most common genomic rearrangements were breakpoints in or around the OGA, NPM3, and FGF8 genes in chromosome band 10q24, and loss of 1p11-p21 and 10q26-qter (all simultaneously present in 6/7 MIFS); a breakpoint in or near TGFBR3 in chromosome 1 was found in four of these tumors. Amplification and overexpression of VGLL3 was a consistent feature in MIFS and MIFS-like tumors with amplicons in 3p11-12. The significant molecular genetic outcome of the recurrent t(1;10) could be loss of genetic material from 1p and 10q. Other recurrent genomic imbalances in MIFS, such as homozygous loss of CDKN2A and 3p- and 13q-deletions, are shared with other sarcomas, suggesting overlapping pathogenetic pathways. This article is protected by copyright. All rights reserved.
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| 4. |
- 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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| 5. |
- 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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| 6. |
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| 7. |
- 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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| 8. |
- Haglund, Cecilia, et al.
(författare)
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An intraosseous myoepithelial carcinoma with a EWSR1::PBX3 fusion
- 2023
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Ingår i: Genes, Chromosomes and Cancer. - : WILEY. - 1045-2257 .- 1098-2264. ; 62:10, s. 607-610
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Tidskriftsartikel (refereegranskat)abstract
- Herein we report a case of an intraosseous myoepithelial carcinoma harboring a EWSR1::PBX3 fusion gene. The patient was a 64-year-old male found to have a 7 cm destructive lesion in the distal ulna with an extraosseous soft tissue component. Microscopic examination of the resected tumor showed a spindle-cell lesion within a sclerotic stroma and intravascular tumor emboli. At higher power the tumor cells showed moderate nuclear atypia with a high mitotic count (20 per mm(2)). Immunohistochemistry revealed diffuse EMA positivity and focal pancytokeratin (AE1/AE3) and S100 expression, consistent with myoepithelial differentiation. NGS using the Oncomine Childhood Cancer Assay (Thermo Fisher Scientific, Inc.) revealed a EWSR1-PBX3 fusion and ABL amplification. The patient subsequently developed local recurrence as well as distant lymph node, lung and vertebral metastases; he is currently awaiting systemic treatment in the context of a clinical trial. In this report, we present a rare case of a skeletal myoepithelial tumor harboring a EWSR1::PBX3 fusion with demonstrated histological and clinical features of malignancy.
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| 9. |
- Ibstedt, Sebastian, et al.
(författare)
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A cryptic EWSR1::DDIT3 fusion in myxoid liposarcoma: Potential pitfalls with FISH and cytogenetics
- 2023
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 62:3, s. 167-170
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Tidskriftsartikel (refereegranskat)abstract
- Myxoid liposarcoma (MLS) is molecularly characterized by fusions involving the DDIT3 gene in chromosome band 12q13; the fusion partner is FUS in band 16p11 in 90–95% of the cases and EWSR1 in band 22q12 in the remaining 5–10%. Hence, molecular studies, often fluorescence in situ hybridization (FISH) for DDIT3 rearrangement, are useful for establishing a correct diagnosis. Although all MLS tumors should have DDIT3 fusions, it is important to be aware of reasons for potential false-negative results. We here present a case of MLS that was negative for FISH for DDIT3, that showed an unexpected t(11;22) at G-banding, but that displayed a characteristic EWSR1::DDIT3 fusion at RNA-sequencing. The results suggest that neoplasia-associated fusions that, due to the transcriptional orientations of the two genes involved, cannot arise through only two double-strand breaks are more likely to be associated with negative FISH-findings and unexpected karyotypes.
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| 10. |
- Javanmardi, Niloufar, et al.
(författare)
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Analysis of ALK, MYCN, and the ALK ligand ALKAL2 (FAM150B/AUG alpha) in neuroblastoma patient samples with chromosome arm 2p rearrangements
- 2020
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Ingår i: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 59:1, s. 50-57
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Tidskriftsartikel (refereegranskat)abstract
- Gain of chromosome arm 2p is a previously described entity in neuroblastoma (NB). This genomic address is home to two important oncogenes in NB-MYCN and anaplastic lymphoma kinase (ALK). MYCN amplification is a critical prognostic factor coupled with poor prognosis in NB. Mutation of the ALK receptor tyrosine kinase has been described in both somatic and familial NB. Here, ALK activation occurs in the context of the full-length receptor, exemplified by activating point mutations in NB. ALK overexpression and activation, in the absence of genetic mutation has also been described in NB. In addition, the recently identified ALK ligand ALKAL2 (previously described as FAM150B and AUG alpha) is also found on the distal portion of 2p, at 2p25. Here we analyze 356 NB tumor samples and discuss observations indicating that gain of 2p has implications for the development of NB. Finally, we put forward the hypothesis that the effect of 2p gain may result from a combination of MYCN, ALK, and the ALK ligand ALKAL2.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Mandahl, Nils, et al.
(författare)
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Giemsa-negative chromosome bands preferentially recombine in cancer-associated translocations and gene fusions
- 2023
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 62:2, s. 61-74
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome abnormalities, in particular translocations, and gene fusions are hallmarks of neoplasia. Although both have been recognized as important drivers of cancer for decades, our knowledge of the characterizing features of the cytobands involved in recombinations is poorly understood. The present study, based on a comparative analysis of 10 442 translocation breakpoints and 30 762 gene fusions comprising 13 864 protein-coding genes, is the most comprehensive evaluation of the interactions of cytobands participating in the formation of such rearrangements in cancer. The major conclusion is that although large G-negative, gene-rich bands are most frequently involved, the greatest impact was seen for staining properties. Thus, 60% of the recombinations leading to the formation of both translocations and fusion genes take place between two G-negative bands whereas only about 10% involve two G-positive bands. There is compelling evidence that G-negative bands contain more genes than dark staining bands and it has previously been shown that breakpoints involved in structural chromosome rearrangements and in gene fusions preferentially affect gene-rich bands. The present study not only corroborates these findings but in addition demonstrates that the recombination processes favor the joining of two G-negative cytobands and that this feature may be a stronger factor than gene content. It is reasonable to assume that the formation of translocations and fusion genes in cancer cells, irrespective of whether they have a pathogenetically significant impact or not, may be mediated by some underlying mechanisms that either favor the origin or provide a selective advantage for recombinations of G-negative cytobands.
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| 15. |
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| 16. |
- Mitra, Shamik, et al.
(författare)
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Amplification of ERBB2 (HER2) in embryonal rhabdomyosarcoma : A potential treatment target in rare cases?
- 2022
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Ingår i: Genes, Chromosomes and Cancer. - : John Wiley & Sons. - 1045-2257 .- 1098-2264. ; 61:1, s. 5-9
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Tidskriftsartikel (refereegranskat)abstract
- The ERBB2 gene encodes a receptor tyrosine kinase also known as HER2. The gene is amplified and overexpressed in one-fifth of breast carcinomas; patients with such tumors benefit from targeted treatment with trastuzumab or other drugs blocking the receptor. In addition, ERBB2 has been shown to be amplified and/or overexpressed in a variety of other malignancies. Notably, both alveolar and embryonal rhabdomyosarcoma (RMS), especially in children, often show increased expression of ERBB2. Although high-level amplification of the gene has not been described in RMS, its frequent expression at the cell surface of RMS cells has been exploited for chimeric antigen receptor T-cell (CAR T)-based treatment strategies. We here describe two cases of pediatric, fusion-negative embryonal RMS with high-level amplification of the ERBB2 gene. One patient is currently treated with conventional chemotherapy for a recently detected standard risk RMS, whereas the other patient died from metastatic disease. Both tumors displayed focal amplicons (210 and 274 Kb, respectively) in chromosome band 17q12, with proximal and distal borders corresponding to those typically seen in breast cancer. In both tumors, the ERBB2 amplicon correlated with high expression at the RNA and protein levels. Thus, breast cancer-like ERBB2 amplification is a very rare, but recurrent feature of pediatric RMS, and should be exploited as an alternative treatment target.
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| 17. |
- Moura-Castro, Larissa H., et al.
(författare)
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Sister chromatid cohesion defects are associated with chromosomal copy number heterogeneity in high hyperdiploid childhood acute lymphoblastic leukemia
- 2021
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 60:6, s. 410-417
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Tidskriftsartikel (refereegranskat)abstract
- High hyperdiploid acute lymphoblastic leukemia (ALL) is one of the most common malignancies in children. The main driver event of this disease is a nonrandom aneuploidy consisting of gains of whole chromosomes but without overt evidence of chromosomal instability (CIN). Here, we investigated the frequency and severity of defective sister chromatid cohesion—a phenomenon related to CIN—in primary pediatric ALL. We found that a large proportion (86%) of hyperdiploid cases displayed aberrant cohesion, frequently severe, to compare with 49% of ETV6/RUNX1-positive ALL, which mostly displayed mild defects. In hyperdiploid ALL, cohesion defects were associated with increased chromosomal copy number heterogeneity, which could indicate increased CIN. Furthermore, cohesion defects correlated with RAD21 and NCAPG mRNA expression, suggesting a link to reduced cohesin and condensin levels in hyperdiploid ALL. Knockdown of RAD21 in an ALL cell line led to sister chromatid cohesion defects, aberrant mitoses, and increased heterogeneity in chromosomal copy numbers, similar to what was seen in primary hyperdiploid ALL. In summary, our study shows that aberrant sister chromatid cohesion is frequent but heterogeneous in pediatric high hyperdiploid ALL, ranging from mild to very severe defects, and possibly due to low cohesin or condensin levels. Cases with high levels of aberrant chromosome cohesion displayed increased chromosomal copy number heterogeneity, possibly indicative of increased CIN. These abnormalities may play a role in the clonal evolution of hyperdiploid pediatric ALL.
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| 18. |
- 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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| 19. |
- Pfisterer, Ulrich, et al.
(författare)
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Single-cell sequencing in translational cancer research and challenges to meet clinical diagnostic needs
- 2021
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 60:7, s. 504-524
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Forskningsöversikt (refereegranskat)abstract
- The ability to capture alterations in the genome or transcriptome by next-generation sequencing has provided critical insight into molecular changes and programs underlying cancer biology. With the rapid technological development in single-cell sequencing, it has become possible to study individual cells at the transcriptional, genetic, epigenetic, and protein level. Using single-cell analysis, an increased resolution of fundamental processes underlying cancer development is obtained, providing comprehensive insights otherwise lost by sequencing of entire (bulk) samples, in which molecular signatures of individual cells are averaged across the entire cell population. Here, we provide a concise overview on the application of single-cell analysis of different modalities within cancer research by highlighting key articles of their respective fields. We furthermore examine the potential of existing technologies to meet clinical diagnostic needs and discuss current challenges associated with this translation.
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| 20. |
- Siegele, Bradford J., et al.
(författare)
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N-terminus DUX4-immunohistochemistry is a reliable methodology for the diagnosis of DUX4-fused B-lymphoblastic leukemia/lymphoma (N-terminus DUX4 IHC for DUX4-fused B-ALL)
- 2022
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 61:8, s. 449-458
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Tidskriftsartikel (refereegranskat)abstract
- B-lymphoblastic leukemia/lymphoma (B-ALL) is the most common pediatric malignancy and the most commonly diagnosed adult lymphoblastic leukemia. Recent advances have broadened the spectrum of B-ALL, with DUX4 gene fusions implicated in a subclass occurring in adolescents and young adults and harboring a favorable prognosis. DUX4 fusions have been challenging to identify. We aimed to determine whether expression of the DUX4 oncoprotein, as detected by targeted immunohistochemistry, might serve as a surrogate for molecular detection of DUX4 fusions in B-ALL. A cohort of investigational B-ALLs was generated with enrichment for DUX4 fusions by the inclusion of cases with characteristic demographic features and immunophenotypic properties. B-ALLs with mutually exclusive cytogenetics were collected. Immunohistochemical staining by a monoclonal antibody raised against the N-terminus of the DUX4 protein was performed. N-DUX4 immunohistochemistry demonstrated strong, crisp nuclear staining in blasts of seven investigational cases, six of which had nucleic acid material available for molecular evaluation. Five of these cases demonstrated RNA-seq DUX4-fusion positivity. One N-DUX4 immunohistochemistry positive case lacked a definitive DUX4-fusion by RNA-seq, though demonstrated a gene expression profile characteristic of DUX4-rearranged B-ALLs, a CD2+ immunophenotype, and a lack of staining by C-terminus DUX4 antibody immunohistochemistry. At least 83.3% [5/6] positive predictive value. N-DUX4 immunohistochemistry was negative in blasts of three RNA-seq DUX4-fusion-negative cases (3/3; 100% negative predictive value). B-ALLs with mutually exclusive cytogenetic profiles were all N-DUX4 negative (0/10, specificity 100%). N-DUX4 immunohistochemistry is reliable for the distinction of DUX4-rearranged B-ALLs from other B-ALLs. We recommend its use for subclassification of B-ALLs in adolescents and young adults and in B-ALLs that remain “not otherwise specified.”.
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| 21. |
- Skaftason, A., et al.
(författare)
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Transcriptome sequencing of archived lymphoma specimens is feasible and clinically relevant using exome capture technology
- 2022
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Ingår i: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 61:1, s. 27-36
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Tidskriftsartikel (refereegranskat)abstract
- Formalin-fixed, paraffin-embedded (FFPE) specimens are an underutilized resource in medical research, particularly in the setting of transcriptome sequencing, as RNA from these samples is often degraded. We took advantage of an exome capture-based RNA-sequencing protocol to explore global gene expression in paired fresh-frozen (FF) and FFPE samples from 16 diffuse large B-cell lymphoma (DLBCL) patients. While FFPE samples generated fewer mapped reads compared to their FF counterparts, these reads captured the same library complexity and had a similar number of genes expressed on average. Furthermore, gene expression demonstrated a high correlation when comparing housekeeping genes only or across the entire transcriptome (r = 0.99 for both comparisons). Differences in gene expression were primarily seen in lowly expressed genes and genes with small or large coding sequences. Using cell-of-origin classifiers and clinically relevant gene expression signatures for DLBCL, FF, and FFPE samples from the same biopsy paired nearly perfectly in clustering analysis. This was further confirmed in a validation cohort of 50 FFPE DLBCL samples. In summary, we found the biological differences between tumors to be far greater than artifacts created as a result of degraded RNA. We conclude that exome capture transcriptome sequencing data from archival samples can confidently be used for cell-of-origin classification of DLBCL samples.
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| 22. |
- Svensson, Sara, et al.
(författare)
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Merged testing for colorectal cancer syndromes and re-evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort
- 2022
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Ingår i: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 61:10, s. 585-591
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 5% of patients with colorectal cancer (CRC) have a Mendelian predisposition for the disease. Identification of the disease-causing genetic variant enables carrier testing and tailored cancer prevention within affected families. To determine the panorama and genetic variation of Mendelian CRC syndromes among referrals at the cancer genetics clinics in Sweden, 850 patients clinically selected for CRC genetic investigation were included in a prospective study that tested for all major hereditary polyposis and nonpolyposis CRC conditions. Genetically defined syndromes were diagnosed in 11% of the patients. Lynch syndrome was predominant (n = 73) followed by familial adenomatous polyposis (n = 12) and MUTYH-associated polyposis (n = 8); the latter of which two patients presented with CRC before polyposis was evident. One patient with a history of adolescent-onset CRC and polyposis had biallelic disease-causing variants diagnostic for constitutional mismatch repair deficiency syndrome. Post-study review of detected variants of unknown clinical significance (n = 129) resulted in the reclassification of variants as likely benign (n = 59) or as diagnostic for Lynch syndrome (n = 2). Our results reveal the panorama of Mendelian CRC syndromes at the cancer genetics clinics in Sweden and show that unified testing for polyposis and nonpolyposis CRC conditions as well as regular reexamination of sequence data improve the diagnostic yield.
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| 23. |
- Sydow, Saskia, et al.
(författare)
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Genomic and transcriptomic characterization of desmoplastic small round cell tumors
- 2021
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 60:9, s. 595-603
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Tidskriftsartikel (refereegranskat)abstract
- Desmoplastic small round cell tumor (DSRCT) is a highly aggressive soft tissue tumor primarily affecting children and young adults. Most cases display a pathognomonic EWSR1-WT1 gene fusion, presumably constituting the primary driver event. Little is, however, known about secondary genetic changes that may affect tumor progression. We here studied 25 samples from 19 DSRCT patients using single nucleotide polymorphism arrays and found that all samples had copy number alterations. The most common imbalances were gain of chromosomes/chromosome arms 1/1q and 5/5p and loss of 6/6q and 16/16q, all occurring in at least eight of the patients. Five cases showed homozygous deletions, affecting a variety of known tumor suppressor genes, for example, CDKN2A and NF1. As almost all patients died of their disease, the impact of individual imbalances on survival could not be evaluated. Global gene expression analysis using mRNA sequencing on fresh-frozen samples from seven patients revealed a distinct transcriptomic profile, with enrichment of genes involved in neural differentiation. Two genes - GJB2 and GAL - that showed higher expression in DSRCT compared to control tumors could be further investigated for their potential as diagnostic markers at the protein level.
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| 24. |
- Wang, Janet, et al.
(författare)
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A cloud-based resource for genome coordinate-based exploration and large-scale analysis of chromosome aberrations and gene fusions in cancer
- 2023
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 62:8, s. 441-448
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Tidskriftsartikel (refereegranskat)abstract
- Cytogenetic analysis provides important information on the genetic mechanisms of cancer. The Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (Mitelman DB) is the largest catalog of acquired chromosome aberrations, presently comprising >70 000 cases across multiple cancer types. Although this resource has enabled the identification of chromosome abnormalities leading to specific cancers and cancer mechanisms, a large-scale, systematic analysis of these aberrations and their downstream implications has been difficult due to the lack of a standard, automated mapping from aberrations to genomic coordinates. We previously introduced CytoConverter as a tool that automates such conversions. CytoConverter has now been updated with improved interpretation of karyotypes and has been integrated with the Mitelman DB, providing a comprehensive mapping of the 70 000+ cases to genomic coordinates, as well as visualization of the frequencies of chromosomal gains and losses. Importantly, all CytoConverter-generated genomic coordinates are publicly available in Google BigQuery, a cloud-based data warehouse, facilitating data exploration and integration with other datasets hosted by the Institute for Systems Biology Cancer Gateway in the Cloud (ISB-CGC) Resource. We demonstrate the use of BigQuery for integrative analysis of Mitelman DB with other cancer datasets, including a comparison of the frequency of imbalances identified in Mitelman DB cases with those found in The Cancer Genome Atlas (TCGA) copy number datasets. This solution provides opportunities to leverage the power of cloud computing for low-cost, scalable, and integrated analysis of chromosome aberrations and gene fusions in cancer.
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