| 1. |
- Bekers, Elise M., et al.
(författare)
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Soft tissue angiofibroma : Clinicopathologic, immunohistochemical and molecular analysis of 14 cases
- 2017
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 56:10, s. 750-757
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Tidskriftsartikel (refereegranskat)abstract
- Soft tissue angiofibroma is rare and has characteristic histomorphological and genetic features. For diagnostic purposes, there are no specific antibodies available. Fourteen lesions (6 females, 8 males; age range 7-67 years) of the lower extremities (12) and trunk (2) were investigated by immunohistochemistry, including for the first time NCOA2. NCOA2 was also tested in a control group of other spindle cell lesions. The known fusion-genes (AHRR-NCOA2 and GTF2I-NCOA2) were examined using RT-PCR in order to evaluate their diagnostic value. Cases in which no fusion gene was detected were additionally analysed by RNA sequencing. All cases tested showed nuclear expression of NCOA2. However, this was not specific since other spindle cell neoplasms also expressed this marker in a high percentage of cases. Other variably positive markers were EMA, SMA, desmin and CD34. STAT6 was negative in the cases tested. By RT-PCR for the most frequently observed fusions, an AHRR-NCOA2 fusion transcript was found in 9/14 cases. GTF2I-NCOA2 was not detected in the remaining cases (n = 3). RNA sequencing revealed three additional positive cases; two harbored a AHRR-NCOA2 fusion and one case a novel GAB1-ABL1 fusion. Two cases failed molecular analysis due to poor RNA quality. In conclusion, the AHRR-NCOA2 fusion is a frequent finding in soft tissue angiofibroma, while GTF2I-NCOA2 seems to be a rare genetic event. For the first time, we report a GAB1-ABL1 fusion in a soft tissue angiofibroma of a child. Nuclear expression of NCOA2 is not discriminating when compared with other spindle cell neoplasms.
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| 2. |
- Biermann, Jana, et al.
(författare)
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Radiation-induced genomic instability in breast carcinomas of the Swedish haemangioma cohort.
- 2019
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 58:9, s. 627-35
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Tidskriftsartikel (refereegranskat)abstract
- Radiation-induced genomic instability (GI) is hypothesized to persist after exposure and ultimately promote carcinogenesis. Based on the absorbed dose to the breast, an increased risk of developing breast cancer was shown in the Swedish haemangioma cohort that was treated with radium-226 for skin haemangioma as infants. Here, we screened 31 primary breast carcinomas for genetic alterations using the OncoScan CNV Plus Assay to assess GI and chromothripsis-like patterns associated with the absorbed dose to the breast. Higher absorbed doses were associated with increased numbers of copy number alterations (CNAs) in the tumour genome and thus a more unstable genome. Hence, the observed dose-dependent GI in the tumour genome is a measurable manifestation of the long-term effects of irradiation. We developed a highly predictive Cox regression model for overall survival based on the interaction between absorbed dose and GI. The Swedish haemangioma cohort is a valuable cohort to investigate the biological relationship between absorbed dose and GI in irradiated humans. This work gives a biological basis for improved risk assessment to minimize carcinogenesis as a secondary disease after radiation therapy. This article is protected by copyright. All rights reserved.
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| 3. |
- Christofer Juhlin, C., et al.
(författare)
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Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene
- 2015
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley: 12 months. - 1045-2257 .- 1098-2264. ; 54:9, s. 542-554
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Tidskriftsartikel (refereegranskat)abstract
- As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. (c) 2015 The Authors. Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.
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| 4. |
- Dirse, Vaidas, et al.
(författare)
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A Population-Based Single Nucleotide Polymorphism Array Analysis of Genomic Aberrations in Younger Adult Acute Lymphoblastic Leukemia Patients
- 2015
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 54:5, s. 326-333
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Tidskriftsartikel (refereegranskat)abstract
- Adult acute lymphoblastic leukemia (ALL) is characterized by a high frequency of abnormal karyotypes some of which are related to outcome. Single nucleotide polymorphism (SNP) array analysis provides a highly sensitive platform to detect large and small genomic aberrations. SNP array profiling data in adult ALL are limited and further systematic studies of this patient group are needed. We performed a population-based SNP array analysis of genomic aberrations and their influence on survival in 66 Lithuanian 18-65 year old ALL patients diagnosed between 2007 and 2013. Most aberrations were detected in chromosome arm 9p, chromosome arm 6q, chromosome arm 13q, and chromosome 17. The recurrently targeted copy number abnormalities involved several leukemia-related genesCDKN2A/B, MLL, IKZF1, PAX5, RB1, TP53, and ETV6. We identified several new recurrent aberrations with possible new target genes: SMARCA4 in 19p13.2, RNASEL in 1q25.3, ARHGEF12 in 11q23.3, and LYL1 in 19p13.2. Aberrations in chromosome 13 and the RB1 gene as well as CDKN2A/B gene status were related to the outcome. (c) 2015 Wiley Periodicals, Inc.
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| 5. |
- Ellberg, Carolina, et al.
(författare)
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Impact of a paternal origin of germline BRCA1/2 mutations on the age at breast and ovarian cancer diagnosis in a Southern Swedish cohort.
- 2015
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 54:1, s. 39-50
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Tidskriftsartikel (refereegranskat)abstract
- Three studies have reported that BRCA1/2 mutations of paternal origin confer an earlier age at breast cancer diagnosis compared with maternal origin. The primary aim of this study was to investigate the impact of parental origin of BRCA1/2 mutations on age at breast and ovarian cancer diagnosis. This study included 577 female BRCA1/2 mutation carriers. All BRCA1/2 mutation carriers belonged to families registered between 1993 and 2011 at the Oncogenetic Clinic at Skånes University Hospital, Lund, Sweden. Cox proportional hazard ratios were used to analyze time to breast or ovarian cancer diagnosis. A novel finding was that carriers of BRCA1 mutations of paternal origin were 4 years older at age of ovarian cancer (P = 0.009) compared with those carrying a BRCA1 mutation of maternal origin. BRCA1 carriers with mutations of paternal origin were 4 years younger at breast cancer diagnosis (P = 0.017) compared with those carrying a BRCA1 mutation of maternal origin, which is in agreement with three previous studies. Both findings were adjusted for of year of inclusion, birth date, and oral contraceptive pill use. No associations between parental origin of BRCA2 mutations and time to breast or ovarian cancer diagnosis were found. An attempt to handle a potential selection bias regarding use of oral contraceptives was made using multiple imputations by chained equations. The observed age difference may allow a greater understanding of mechanisms associated with the differences in cancer penetrance in BRCA1/2 mutation carriers, some of which may depend on paternal origin. © 2014 Wiley Periodicals, Inc.
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| 6. |
- Espersen, A. D. L., et al.
(författare)
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Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is associated with infancy and trisomy 19: Data from Nordic Society for Pediatric Hematology and Oncology (NOPHO-AML) and review of the literature
- 2018
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Ingår i: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 57:7, s. 359-365
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Tidskriftsartikel (refereegranskat)abstract
- The t(7;12)(q36;p13) (MNX1/ETV6) is not included in the WHO classification but has been described in up to 30% of acute myeloid leukemia (AML) in children <2 years and associated with a poor prognosis. We present the clinical and cytogenetics characteristics of AML cases with t(7;12)(p36;p13). A literature review identified 35 patients with this translocation, published between 2000 and 2015. Outcome data were available in 22 cases. The NOPHO-AML (Nordic Society for Pediatric Hematology and Oncology) database contained 651 patients with AML from 1993 to 2014 and seven (1.1%) had the translocation. The t(7;12) was only present in patients <2 years of age (median age 6 months) but none was diagnosed as newborn. These patients constituted 4.3% of the patients <2 years of age. There was a strong association with trisomy 19 (literature: 86%, NOPHO: 100%) and +8 (literature: 19%, NOPHO: 14%). Seventeen of 22 patients from the literature with t(7;12) and four of seven patients from the NOPHO database suffered from relapse. The patients with t(7;12) had a 3-year event free survival of 24% (literature) vs. 43% (NOPHO) and a 3-year overall survival of 42% (literature) vs. 100% (NOPHO). None of the NOPHO patients was treated with hematopoietic stem cell transplantation (HSCT) in first complete remission. Relapse was frequent but the salvage rate using HSCT was high. We conclude that t(7;12)(q36;13) is a unique subgroup of childhood AML with presentation before 2 years of age with most cases being associated with +19.
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| 7. |
- 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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| 8. |
- Gisselsson, David, et al.
(författare)
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Clonal evolution through genetic bottlenecks and telomere attrition : Potential threats to in vitro data reproducibility
- 2019
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Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 58:7, s. 452-461
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Forskningsöversikt (refereegranskat)abstract
- Tissue cultures of immortalized human cells, also known as established cell lines, are broadly accessible and cost-efficient tools for biomedical research. We here review potential genetic sources of systematic error in cell line experiments due to clonal evolution in vitro. In particular, the authors highlight alterations in telomere function over prolonged culture and population bottlenecks, respectively, as two commonly overlooked phenomena that can result in significant alterations in cell line genotypes over just one or a few passages in vitro. These alterations may include changes in mutation status of oncogenes and large scale chromosomal imbalances. We introduce a simple list of factors to be avoided in order to reduce the risk of data misinterpretation due to clonal evolution, including unacknowledged in vitro selection pressures, prolonged culture per se, harsh population size reductions, experiments at early phases after establishment, and the employment of cell lines not sufficiently analyzed by high resolution genetic techniques.
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| 9. |
- Hemminki, Kari, et al.
(författare)
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Metabolic gene variants associated with chromosomal aberrations in healthy humans.
- 2015
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 54:4, s. 260-266
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Tidskriftsartikel (refereegranskat)abstract
- Nonspecific chromosomal aberrations (CAs) are found in about 1% of lymphocytes drawn from healthy individuals. They include chromosome-type aberrations (CSAs), which are increased in exposure to ionizing radiation, and chromatid-type aberrations (CTAs) which in experimental systems are formed by DNA binding carcinogens and mutagens. The frequency of CAs is associated with the risk of cancer, but the causes of CAs in general population are unknown. Here, we want to test whether variants in metabolic genes associate with CAs in healthy volunteers. Cases were considered those whose total CA (CAtot) frequency was >2% and for CSA and CTA the limit was >1%. Controls had lower frequencies of CAs. Functional polymorphisms in seven genes were selected for analysis: cytochrome P450 1B1 (CYP1B1), epoxide hydrolase 1 (EPHX1), NAD(P)H:quinone oxidoreductase 1 (NQO1), each coding for phase 1 enzymes, and glutathione S-transferase P1 (GSTP1), glutathione S-transferases M1 (GSTM1) and T1 (GSTT1), coding for enzymes which conjugate reactive metabolites, that is, phase 2 enzymes. The number of volunteers genotyped for each gene varied from 550 to 1,500. Only EPHX1 was individually associated with CAtot; high activity genotypes decreased CAtot. A total of six significant (P < 0.01) pair-wise interactions were observed, most including a GST variant as one of the pair. In all genotype combinations with significant odds ratios for CAs a GST variant was involved. The present data provide evidence that variants in genes coding for metabolic enzymes, which individually have small effects, interact and are associated with CA frequencies in peripheral lymphocytes of healthy volunteers. © 2015 Wiley Periodicals, Inc.
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| 10. |
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