| 1. |
- Brekke, Helge R, et al.
(författare)
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Genomic Changes in Chromosomes 10, 16, and X in Malignant Peripheral Nerve Sheath Tumors Identify a High-Risk Patient Group.
- 2010
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 28, s. 1573-1582
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The purpose of this study was to identify genetic aberrations contributing to clinical aggressiveness of malignant peripheral nerve sheath tumors (MPNSTs). PATIENTS AND METHODS: Samples from 48 MPNSTs and 10 neurofibromas were collected from 51 patients with (n = 31) or without (n = 20) neurofibromatosis type 1 (NF1). Genome-wide DNA copy number changes were assessed by chromosomal and array-based comparative genomic hybridization (CGH) and examined for prognostic significance. For a subset of 20 samples, RNA microarray data were integrated with the genome data to identify potential target genes. RESULTS: Forty-four (92%) MPNSTs displayed DNA copy number changes (median, 18 changes per tumor; range, 2 to 35 changes). Known frequent chromosomal gains at chromosome arms 8q (69%), 17q (67%), and 7p (52%) and losses from 9p (50%), 11q (48%), and 17p (44%) were confirmed. Additionally, gains at 16p or losses from 10q or Xq identified a high-risk group with only 11% 10-year disease-specific survival (P = .00005). Multivariate analyses including NF1 status, tumor location, size, grade, sex, complete remission, and initial metastatic status showed that the genomic high-risk group was the most significant predictor of poor survival. Several genes whose expression was affected by the DNA copy number aberrations were identified. CONCLUSION: The presence of specific genetic aberrations was strongly associated with poor survival independent of known clinical risk factors. Conversely, within the total patient cohort with 34% 10-year disease-specific survival, a low-risk group was identified: without changes at chromosomes 10q, 16p, or Xq in their MPNSTs, the patients had 74% 10-year survival.
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| 2. |
- Du, Likun, et al.
(författare)
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Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis
- 2012
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 209:2, s. 291-305
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Tidskriftsartikel (refereegranskat)abstract
- Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.
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| 3. |
- Osorio, Ana, et al.
(författare)
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DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
- 2014
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7×10-3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8×10-3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
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| 4. |
- de Miranda, Noel F. C. C., et al.
(författare)
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Exome sequencing reveals novel mutation targets in diffuse large B-cell lymphomas derived from Chinese patients
- 2014
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 124:16, s. 2544-2553
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Tidskriftsartikel (refereegranskat)abstract
- Next-generation sequencing studies on diffuse large B-cell lymphomas (DLBCLs) have revealed novel targets of genetic aberrations but also high intercohort heterogeneity. Previous studies have suggested that the prevalence of disease subgroups and cytogenetic profiles differ between Western and Asian patients. To characterize the coding genome of Chinese DLBCL, we performed whole-exome sequencing of DNA derived from 31 tumors and respective peripheral blood samples. The mutation prevalence of B2M, CD70, DTX1, LYN, TMSB4X, and UBE2A was investigated in an additional 105 tumor samples. We discovered 11 novel targets of recurrent mutations in DLBCL that included functionally relevant genes such as LYN and TMSB4X. Additional genes were found mutated at high frequency (>= 10%) in the Chinese cohort including DTX1, which was the most prevalent mutation target in the Notch pathway. We furthermore demonstrated that mutations in DTX1 impair its function as a negative regulator of Notch. Novel and previous unappreciated targets of somatic mutations in DLBCL identified in this study support the existence of additional/alternative tumorigenic pathways in these tumors. The observed differences with previous reports might be explained by the genetic heterogeneity of DLBCL, the germline genetic makeup of Chinese individuals, and/or exposure to distinct etiological agents.
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| 5. |
- Lovf, Marthe, et al.
(författare)
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Assessment of Fusion Gene Status in Sarcomas Using a Custom Made Fusion Gene Microarray
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Sarcomas are relatively rare malignancies and include a large number of histological subgroups. Based on morphology alone, the differential diagnoses of sarcoma subtypes can be challenging, but the identification of specific fusion genes aids correct diagnostication. The presence of individual fusion products are routinely investigated in Pathology labs. However, the methods used are time-consuming and based on prior knowledge about the expected fusion gene and often the most likely break-point. In this study, 16 sarcoma samples, representing seven different sarcoma subtypes with known fusion gene status from a diagnostic setting, were investigated using a fusion gene microarray. The microarray was designed to detect all possible exon-exon breakpoints between all known fusion genes in a single analysis. An automated scoring of the microarray data from the 38 known sarcoma-related fusion genes identified the correct fusion gene among the top-three hits in 11 of the samples. The analytical sensitivity may be further optimised, but we conclude that a sarcoma-fusion gene microarray is suitable as a time-saving screening tool to identify the majority of the correct fusion genes.
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