Detection of cryptic and variant IGH-MYC rearrangements in high-grade non-Hodgkin’s lymphoma by fluorescence
Department of Haematology and Department of Cytogenetics, GSTS Pathology, Guy's and St. Thomas NHS Foundation Trust, Great Maze Pond, London, SE1 9RT UK.Cancer genetics and cytogenetics (Impact Factor: 1.93). 04/2010; 198(1):71-5. DOI: 10.1016/j.cancergencyto.2009.12.010
In recent years it has become increasingly evident that MYC rearrangements are not confined to classical Burkitt lymphoma (BL), but also occur in diffuse large B-cell lymphoma (DLBCL) and in the new subtype, "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL" (BCLU), which was recently described in the 2008 revision of the World Health Organization classification. The accurate identification of MYC rearrangements in these three subtypes of high-grade lymphoma is becoming increasingly critical both in terms of diagnosis of classical BL and in light of the prognostic implications in cases of DLBCL and BCLU. We describe three cases of high-grade lymphoma in which cryptic insertion events, resulting in clinically significant IGH-MYC rearrangements, were detectable using an IGH/MYC three-color, dual-fusion fluorescence in situ hybridization (FISH) probe set, but were not detected using break-apart MYC FISH probes, thus highlighting the limitations of using break-apart probes as a stand-alone test, particularly with the increased use of interphase FISH analysis of formalin-fixed, paraffin-embedded tissue sections in the diagnostic work-up of these patients.
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ABSTRACT: Kluin P & Schuuring E (2011) Histopathology 58, 128–144 Molecular cytogenetics of lymphoma: where do we stand in 2010? For the past 20 years most malignant lymphomas have been classified as clinicopathological entities, each with its own combination of clinical, morphological, immunophenotypic and molecular genetic characteristics. Molecular and cytogenetic abnormalities can be detected by a wide range of techniques, ranging from conventional karyotyping to single nucleotide polymorphism analysis. In this review, we consider the common genetic abnormalities found in lymphoma and discuss the advantages and disadvantages of individual techniques used in their detection. Finally, we discuss briefly possible novel developments in the field of lymphoma diagnostics.
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ABSTRACT: Whole-genome sequencing is becoming increasingly available for research purposes, but it has not yet been routinely used for clinical diagnosis. To determine whether whole-genome sequencing can identify cryptic, actionable mutations in a clinically relevant time frame. DESIGN, SETTING, AND PATIENT: We were referred a difficult diagnostic case of acute promyelocytic leukemia with no pathogenic X-RARA fusion identified by routine metaphase cytogenetics or interphase fluorescence in situ hybridization (FISH). The case patient was enrolled in an institutional review board-approved protocol, with consent specifically tailored to the implications of whole-genome sequencing. The protocol uses a "movable firewall" that maintains patient anonymity within the entire research team but allows the research team to communicate medically relevant information to the treating physician. Clinical relevance of whole-genome sequencing and time to communicate validated results to the treating physician. Massively parallel paired-end sequencing allowed identification of a cytogenetically cryptic event: a 77-kilobase segment from chromosome 15 was inserted en bloc into the second intron of the RARA gene on chromosome 17, resulting in a classic bcr3 PML-RARA fusion gene. Reverse transcription polymerase chain reaction sequencing subsequently validated the expression of the fusion transcript. Novel FISH probes identified 2 additional cases of t(15;17)-negative acute promyelocytic leukemia that had cytogenetically invisible insertions. Whole-genome sequencing and validation were completed in 7 weeks and changed the treatment plan for the patient. Whole-genome sequencing can identify cytogenetically invisible oncogenes in a clinically relevant time frame.
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