Cryptic ETV6-PDGFRB fusion in a highly complex rearrangement of chromosomes 1, 5, and 12 due to a chromothripsis-like event in a myelodysplastic syndrome/myeloproliferative neoplasm (original) (raw)
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Genomic and clinical findings in myeloid neoplasms with PDGFRB rearrangement
Annals of Hematology, 2021
Platelet-derived growth factor receptor B (PDGFRB) gene rearrangements define a unique subgroup of myeloid and lymphoid neoplasms frequently associated with eosinophilia and characterized by high sensitivity to tyrosine kinase inhibition. To date, various PDGFRB/5q32 rearrangements, involving at least 40 fusion partners, have been reported. However, information on genomic and clinical features accompanying rearrangements of PDGFRB is still scarce. Here, we characterized a series of 14 cases with a myeloid neoplasm using cytogenetic, single nucleotide polymorphism array, and next-generation sequencing. We identified nine PDGFRB translocation partners, including the KAZN gene at 1p36.21 as a novel partner in a previously undescribed t(1;5)(p36;q33) chromosome change. In all cases, the PDGFRB recombination was the sole cytogenetic abnormality underlying the phenotype. Acquired somatic variants were mainly found in clinically aggressive diseases and involved epigenetic genes (TET2, DNMT...
The role of chromosomal alterations in human cancer development
Journal of Cellular Biochemistry, 2007
Cancer cells become unstable and compromised because several cancer-predisposing mutations affect genes that are responsible for maintaining the genomic instability. Several factors influence the formation of chromosomal rearrangements and consequently of fusion genes and their role in tumorigenesis. Studies over the past decades have revealed that recurring chromosome rearrangements leading to fusion genes have a biological and clinical impact not only on leukemias and lymphomas, but also on certain epithelial tumors. With the implementation of new and powerful cytogenetic and molecular techniques the identification of fusion genes in solid tumors is being facilitated. Overall, the study of chromosomal translocations have revealed several recurring themes, and reached important insights into the process of malignant transformation. However, the mechanisms behind these translocations remain unclear. A more thorough understanding of the mechanisms that cause translocations will be aided by continuing characterization of translocation breakpoints and by developing in vitro and in vivo model systems that can generate chromosome translocation.
Rare gene fusion rearrangement SPTNB1-PDGFRB in an atypical myeloproliferative neoplasm
Molecular Cytogenetics
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia recognizes a distinct class of myeloid and lymphoid tumors with eosinophilia-related proliferations associated with specific gene rearrangements, one of which involves rearrangements of platelet-derived growth factor receptor B (PDGFRB) gene. We report a case of a rare PDGFRB rearrangement with SPTNB1 (spectrin beta, nonerythrocytic 1) that presented as atypical myeloproliferative neoplasm.
Genes, Chromosomes and Cancer, 1998
Several partner genes on different chromosomes have been reported to be fused with the ETV6 gene (located in chromosome band 12p13), with different breakpoints and different frequencies, in various hematologic malignancies, particularly acute myeloid and lymphoid leukemias and myelodysplastic syndromes. By using FISH and molecular analyses, we have analyzed five different pediatric and adult patients carrying cytogenetic abnormalities involving 12p13. Our findings demonstrate that ETV6 was rearranged in all the cases analyzed. In particular, ETV6 was disrupted by translocations with chromosomal bands 7q22, 7q36, 9q11, and 13q12, not previously described as partners of ETV6 in translocations, thus extending its promiscuity in rearranging with different partner genes.
Leukemia, 2006
Fluorescence in situ hybridization and comparative genomic hybridization characterized 6p rearrangements in eight primary and in 10 secondary myeloid disorders (including one patient with Fanconi anemia) and found different molecular lesions in each group. In primary disorders, 6p abnormalities, isolated in six patients, were highly heterogeneous with different breakpoints along the 6p arm. Reciprocal translocations were found in seven. In the 10 patients with secondary acute myeloid leukemia/myelodysplastic syndrome (AML/MDS), the short arm of chromosome 6 was involved in unbalanced translocations in 7. The other three patients showed full or partial trisomy of the 6p arm, that is, i(6)(p10) (one patient) and dup(6)(p) (two patients). In 5/7 patients with unbalanced translocations, DNA sequences were overrepresented at band 6p21 as either cryptic duplications (three patients) or cryptic low-copy gains (two patients). In the eight patients with cytogenetic or cryptic 6p gains, we identified a common overrepresented region extending for 5-6 megabases from the TNF gene to the ETV-7 gene. 6p abnormalities were isolated karyotype changes in four patients. Consequently, in secondary AML/MDS, we hypothesize that 6p gains are major pathogenetic events arising from acquired and/ or congenital genomic instability.
American Journal of Hematology, 2015
confirm that mutant PDGFRB is indeed the driver mutation in PDGFRB rearranged myeloid neoplasms, consistent with the robust treatment responses with imatinib, thereby constituting a unique stem cell disorder that should continue to be classified separately. al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 2002;347:481-487. 3. Pardanani A, Ketterling RP, Li CY, et al. FIP1L1-PDGFRA in eosinophilic disorders: Prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature. Leuk Res 2006;30:965-970. 4. Cheah CY, Burbury K, Apperley JF, et al. Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib. Blood 2014;123: 3574-3577. 5. Gotlib J. World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management. Am J Hematol 2014;89:325-337. 6. Wassie EA, Itzykson R, Lasho TL, et al. Molecular and prognostic correlates of cytogenetic abnormalities in chronic myelomonocytic leukemia: A Mayo Clinic-French Consortium Study. Am J Hematol 2014;89:1111-1115. 7. Golub TR, Barker GF, Lovett M, et al. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994; 77:307-316. 8. Parikh SA, Tefferi A. Chronic myelomonocytic leukemia: 2013 update on diagnosis, risk stratification, and management. Am J Hematol 2013;88:967-974.
Frequent chromatin rearrangements in myelodysplastic syndromes--what stands behind?
Folia biologica, 2014
Myelodysplastic syndromes (MDS) represent a clinically and genetically heterogeneous group of clonal haematopoietic diseases characterized by a short survival and high rate of transformation to acute myeloid leukaemia (AML). In spite of this variability, MDS is associated with typical recurrent non-random cytogenetic defects. Chromosomal abnormalities are detected in the malignant bone-marrow cells of approximately 40-80 % of patients with primary or secondary MDS. The most frequent chromosomal rearrangements involve chromosomes 5, 7 and 8. MDS often shows presence of unbalanced chromosomal changes, especially large deletions [del(5), del(7q), del(12p), del(18q), del(20q)] or losses of whole chromosomes (7 and Y). The most typical cytogenetic abnormality is a partial or complete deletion of 5q- that occurs in roughly 30 % of all MDS cases either as the sole abnormality or in combination with other aberrations as a part of frequently complex karyotypes. The mechanisms responsible for...
1998
Thirty-two hematologic malignancies-nine with cytogenetically identified 12p abnormalities and 23 with whole or partial losses of chromosome 12-were selected for fluorescence in situ hybridization (FISH) investigations of 12p. These analyses revealed structural 12p changes, such as translocations, deletions, insertions, inversions and amplification, in 20 cases. ETV6 rearrangements were detected in three acute leukemias. One acute undifferentiated leukemia had t(4;12)(q12;p13) as the sole anomaly. The second case, an acute myeloid leukemia (AML), displayed complex abnormalities involving, among others, chromosomes 9 and 12. The third case, also an AML, had an insertion of the distal part of ETV6 into chromosome arm 11q and into multiple ring chromosomes, which also contained chromosome 11 material, resulting in an amplification of a possible fusion gene. The fusion partners in these cases remain to be identified. Thirty-one additional breakpoints on 12p could be characterized in detail. The majority of these breaks were shown to result in interchromosomal rearrangements, possibly indicating the location of hitherto unrecognized genes of importance in the pathogenesis of hematologic malignancies. The FISH analyses disclosed terminal or interstitial 12p deletions in 18 cases. Seven myeloid malignancies showed deletions restricted to a region, including ETV6 and CDKN1B, which has been reported to be frequently lost in leukemias. In four cases, the deletions involved both these genes, whereas two AML displayed loss of CDKN1B but not ETV6, supporting previously reported findings indicating a region of deletion not including this gene. However, one myelodysplastic syndrome lacked one copy of ETV6 but not CDKN1B. Hence, we suggest a minimal region of deletion on 12p located between the ETV6 and CDKN1B genes.
Genomic alterations in myeloid neoplasms with novel, apparently balanced translocations
Cancer genetics, 2011
Characterization of gross chromosomal rearrangements, particularly translocations in neoplasms, has proven to be valuable in patient management by aiding in diagnosis, defining prognosis, and leading to new therapeutic interventions. In this report, we investigate two apparently balanced translocations, t(6;17)(q23.3;p13.3) and t(2;13)(p21;q14.11), in patients with myeloid neoplasms and uncover concomitant microdeletions associated with the breakpoints. Breakpoint mapping by fluorescence in situ hybridization (FISH) detected deletions at or adjacent to all breakpoints. Subsequently, array comparative genomic hybridization on the 244 K Agilent platform refined the deletion boundaries, revealing a 1.7 Mb deletion directly adjacent to the 6q23.3 breakpoint, and a 562 kb deletion at 17p13.3 in the first case. The second case was found to harbor a 195 kb deletion at 2p21 and a 1.4 Mb deletion distal to the 13q breakpoint at 13q14.3. Additionally, a 133 kb deletion within the breakpoint r...