RESUMEN
Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A /B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2 R172 mutation. CN losses were enriched in genes regulating PI3K-AKT-mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.
Asunto(s)
Variaciones en el Número de Copia de ADN , Linfoma de Células T Periférico/genética , Oncogenes , Femenino , Factor de Transcripción GATA3/genética , Perfilación de la Expresión Génica , Humanos , Linfadenopatía Inmunoblástica/genética , Linfoma de Células T Periférico/clasificación , Masculino , Mutación , Proteínas de Dominio T Box/genéticaRESUMEN
PURPOSE: The identification of clinically relevant genomic dosage anomalies assists in accurate diagnosis, prognosis, and medical management of affected individuals. Technological advancements within the field, such as the advent of microarray, have markedly increased the resolution of detection; however, clinical laboratories have maintained conventional techniques for confirmation of genomic imbalances identified by microarray to ensure diagnostic accuracy. In recent years the utility of this confirmatory testing of large-scale aberrations has been questioned but has not been scientifically addressed. METHODS: We retrospectively reviewed 519 laboratory cases with genomic imbalances meeting reportable criteria by microarray and subsequently confirmed with a second technology, primarily fluorescence in situ hybridization. RESULTS: All genomic imbalances meeting reportable criteria detected by microarray were confirmed with a second technology. Microarray analysis generated no false-positive results. CONCLUSION: Confirmatory testing of large-scale genomic imbalances (deletion of ≥150 kb, duplication of ≥500 kb) solely for the purpose of microarray verification may be unwarranted. In some cases, however, adjunct testing is necessary to overcome limitations inherent to microarray. A recommended clinical strategy for adjunct testing following identified genomic imbalances using microarray is detailed.
Asunto(s)
Desequilibrio Alélico , Genómica , Variaciones en el Número de Copia de ADN , Dosificación de Gen , Duplicación de Gen , Genoma Humano , Genómica/métodos , Genómica/normas , Humanos , Hibridación Fluorescente in Situ , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Polimorfismo de Nucleótido Simple , Reproducibilidad de los Resultados , Estudios Retrospectivos , Eliminación de SecuenciaRESUMEN
The use of aCGH has improved our ability to find subtle cytogenetic abnormalities as well as to find more precise information in patients with previously known abnormalities. In addition, it has allowed more specific genotype-phenotype correlation. In this report we describe a patient with a chromosomal deletion initially diagnosed with conventional cytogenetic analysis which was redemonstrated and more specifically described upon aCGH analysis. Our patient is a 12-year-old female born to a 26-year-old G1P0 mother. She was noted as a neonate to have a bilateral cleft lip and cleft palate, abnormal external ears, dysmorphic facies, and moderate to severe hearing loss. She has subsequently shown developmental delay, hyperreflexia, seizures, hyperactivity, and absence of speech. Chromosomal analysis showed deletion of 7q34q36.1. FISH studies confirmed the deletion was interstitial. Parental chromosomes were performed and did not show any cytogenetic abnormalities. aCGH was recently performed for the patient to further characterize the breakpoints of the deletion and confirmed the deletion was interstitial and of 13.2 Mb in size. Both proximal and terminal 7q deletion show a different phenotype than that of our patient. A number of patients with similar deletions have been found and while significant variability is observed, a number of findings appear to be common to deletions in this region. Therefore, we feel that distal interstitial deletions of chromosome 7q represent a recognizable phenotype and could be considered a separate deletion syndrome.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 7 , Labio Leporino/genética , Fisura del Paladar/genética , Discapacidades del Desarrollo/genética , Pérdida Auditiva/genética , Niño , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , SíndromeRESUMEN
Array comparative genomic hybridization has led to the identification of new syndromes by identifying genomic imbalances not detectable by standard karyotyping methods and by allowing correlations with physical findings. Deletions in the 17p13.1 region have been reported in patients with dysmorphic features and developmental delay but a consistent phenotype has yet to emerge. This report describes two unrelated patients with a characteristic phenotype associated with overlapping de novo deletions in the distal region of 17p13.1 detected with array comparative genomic hybridization and confirmed by real-time PCR. These patients share remarkably similar clinical features including microcephaly, mild developmental delay, generalized joint laxity, and a body posture with knee and elbow flexion and hands held in midline. They have distinctive facial features which include long midface with retrognathia with overbite, and protruding ears. The deletions in both patients are the smallest ever reported in this region (approximately 252 and 219 kb). The overlapping region contains 18 genes. Various isolated deletions of the 17p13.1 region have been reported previously without delineation of a consistent phenotype. We propose that the described microdeletions in the distal portion of 17p13.1 represent a novel microdeletion syndrome.
Asunto(s)
Cromosomas Humanos Par 17 , Facies , Eliminación de Gen , Discapacidad Intelectual/genética , Microcefalia/genética , Secuencia de Bases , Niño , Cartilla de ADN , Femenino , Humanos , Masculino , Fenotipo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Males with duplication of the Xq28 region, including methyl CpG-binding protein 2 (MECP2), exhibit a characteristic phenotype, including developmental delay, intellectual disability, limited or absent speech, limited or absent ambulation, and recurrent respiratory infections. We report six males with MECP2 duplications identified using array comparative genomic hybridization. The minimal sizes of these duplications range from â¼0.08 to 14.13 Mb, which, to the best of our knowledge, are respectively the smallest and largest minimal size duplications molecularly characterized to date. Adjunct metaphase fluorescence in situ hybridization analysis further classified these duplications as tandem or as products of complex chromosomal rearrangements. Specifically, one complex rearrangement was described as a der(12)t(X;12)(q28;q24.33), which is the first report of a translocation involving MECP2 on Xq and chromosome 12. The other complex rearrangement was described as a rec(X)dup(Xq)inv(X)(p22.32q28)mat. Synthesis of the dysmorphic features identified in individuals with rec(X) chromosomes, including deletions in the pseudoautosomal region 1 (PAR1) at Xp22.33/Yp11.3 and duplications of the distal Xq region including MECP2, revealed a high prevalence of undescended testes (7/8) and micropenis (3/8) in this cohort. Given that micropenis is rare in the general population, but present in 38% of individuals in this cohort, a dosage anomaly at one or both loci may be a significant risk factor for this condition. Therefore, we recommend microarray testing for patients with unexplained micropenis, particularly when accompanied by other phenotypic anomalies.
Asunto(s)
Cromosomas Humanos X , Duplicación de Gen , Proteína 2 de Unión a Metil-CpG/genética , Translocación Genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Niño , Preescolar , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , MasculinoRESUMEN
The clinical implications of deletions within chromosome 14q32 in CLL pathogenesis remain unclear. We examined the frequency of 14q32 deletions among CLL cases by karyotype and FISH, categorized the variation using genomic microarray, and assessed the prognostic impact by time-to-first-treatment (TTFT) analysis. A 14q32 abnormality was detected in 35 % (245/698) of cases, with the majority containing a 5' partial telomeric 14q32 deletion. These deletions within the IGH variable region (35/40) ranged from 236 kb to 1.4 Mb involving FAM30A, ADAM6, LINC00226, and LINC00221. The 214 kb minimum deleted region implicated in CLL pathogenesis encompassed LINC00221. Cases with a 14q32 deletion had a shorter median TTFT compared to cases with a sole deletion/nullisomy 13q, a good prognostic indicator, and longer than cases with a sole deletion of 11q or 17p, conferring an unfavorable prognosis. This investigation underscores the importance of comprehensive testing to apprehend the implications of 14q32 deletions in CLL.
Asunto(s)
Biomarcadores de Tumor/genética , Deleción Cromosómica , Cromosomas Humanos Par 14/genética , Leucemia Linfocítica Crónica de Células B/patología , Análisis Citogenético , Humanos , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/genética , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: Cytogenetic investigations are useful for etiologic determinations of mental retardation, developmental delay, multiple congenital anomalies, and pregnancy complications; however, the causes remain elusive in a majority of cases despite high-resolution cytogenetic studies and multiple fluorescence in situ hybridization examinations. Array-based comparative genomic hybridization has the ability to examine the genome at a higher resolution and may yield an increased detection of genetic abnormalities. The purpose of this study was to assess the use of array-based comparative genomic hybridization in a clinical genetics setting. METHODS: DNA from 1176 patients was analyzed using a bacterial artificial chromosome array-based comparative genomic hybridization platform. All abnormal cases were confirmed by fluorescence in situ hybridization and parental studies were completed when possible. RESULTS: Of the 1176 patients included in this survey, 163 showed a genomic imbalance identified by array-based comparative genomic hybridization. Of these 163 cases, 116 had a clinically relevant genetic abnormality. A total of 9.8% (116 of 1176 cases) were determined to exhibit a causative genomic imbalance. Twenty-five of the 116 abnormal cases had a previously identified cytogenetic abnormality yielding an increased detection rate of 7.9% (91 of 1146) in cases with normal or no cytogenetics. CONCLUSION: Array-based comparative genomic hybridization increases the overall abnormality detection rate, thus improving the diagnostic potential of clinical cytogenetics investigations.