RESUMEN
The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.
Asunto(s)
Antígeno Ki-1/genética , Linfoma Anaplásico Cutáneo Primario de Células Grandes/genética , Papulosis Linfomatoide/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias Cutáneas/genética , TYK2 Quinasa/genética , Western Blotting , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Hibridación Fluorescente in Situ , Antígeno Ki-1/metabolismo , Linfoma Anaplásico Cutáneo Primario de Células Grandes/metabolismo , Linfoma Anaplásico Cutáneo Primario de Células Grandes/patología , Papulosis Linfomatoide/metabolismo , Papulosis Linfomatoide/patología , Mutación , Proteínas Nucleares/metabolismo , Nucleofosmina , Fusión de Oncogenes , Proteínas de Fusión Oncogénica/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , TYK2 Quinasa/metabolismo , Transcriptoma/genéticaRESUMEN
BACKGROUND: Rearrangements involving the anaplastic lymphoma kinase (ALK) gene are present in approximately 5% of lung adenocarcinomas. Crizotinib is approved for the treatment of lung adenocarcinomas harboring ALK rearrangements. Patients with advanced stage lung cancer are not candidates for surgical resection of their primary tumors. For these patients, cytologic specimens often represent the only diagnostic tissue available. Cell blocks (CBs) are routinely used for molecular studies; however, insufficient CB cellularity can impede the performance of these assays. METHODS: Thirty-two cytology cases of lung adenocarcinomas were analyzed by fluorescence in situ hybridization (FISH) for ALK rearrangements. Diff-Quik-stained smears were examined to identify tumor cell-enriched areas that were marked using a diamond-tipped scribe. Paired ALK rearrangement FISH was performed using smears and CBs in each case. RESULTS: An ALK rearrangement was detected on direct smears and CB sections in 5 (16%) and 4 (13%), respectively, of the 32 cases studied. Concordant FISH results for smears and CBs were observed in 31 (97%) of 32 cases. In the 1 discordant case, an ALK rearrangement was detected on the direct smear but not in the CB. Reverse transcriptase-polymerase chain reaction analysis of this CB revealed the presence of an EML4-ALK rearrangement, thereby confirming a false-negative FISH result in the CB. CONCLUSIONS: Stained cytologic direct smears can be effectively used for ALK rearrangement analysis by FISH. This approach represents a useful safeguard when insufficient CB cellularity is encountered and could prevent delays in treatment in this era of precision medicine.
Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Citodiagnóstico , Reordenamiento Génico , Neoplasias Pulmonares/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas Receptoras/genética , Adenocarcinoma/diagnóstico , Quinasa de Linfoma Anaplásico , Humanos , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/diagnóstico , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Receptionists act as gatekeepers to GPs, and thus are often placed in situations of conflict. However, there is a lack of research in this area. OBJECTIVE: The purpose of this study was to identify the incidence and associations of verbal and physical abuse against primary care receptionists, both pre- and post-'zero tolerance'. METHODS: A postal questionnaire was designed, piloted and sent to all reception staff in 50 randomly selected general practices in Leeds. The primary purpose was to identify any verbal or physical abuse experienced in the 12 months prior to the survey and assess the association between abuse experienced and deprivation. RESULTS: Seventy percent of receptionists completed and returned the questionnaire. Over two-thirds of receptionists had experienced verbal abuse in the last year. During the same time period, 60% reported telephone abuse and 55% reported face to face abuse. The incidence of abuse was higher in the year prior to the study than in the preceding period. Practice deprivation was identified as a significant factor for verbal abuse (P = 0.003). CONCLUSION: Verbal abuse against receptionists is significantly associated with the level of deprivation of the practice area. There is no evidence that 'zero tolerance' led to a reduction in abuse experienced by primary care receptionists. All primary care receptionists should receive adequate training on managing abuse.