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New generation sequencing of targeted genes in the classical and the variant form of hairy cell leukemia highlights mutations in epigenetic regulation genes

2018; Impact Journals LLC; Volume: 9; Issue: 48 Linguagem: Inglês

10.18632/oncotarget.25601

1949-2553

Elsa Maître, Philìppe Bertrand, Catherine Maingonnat, Pierre‐Julien Viailly, Margaux Wiber, Dina Naguib, Véronique Salaün, Édouard Cornet, Gandhi Damaj, Brigitte Sola, Fabrice Jardin, Xavier Troussard,

Ubiquitin and proteasome pathways

// Elsa Maitre 1 , Philippe Bertrand 2 , Catherine Maingonnat 2 , Pierre-Julien Viailly 2 , Margaux Wiber 3 , Dina Naguib 3 , Véronique Salaün 3 , Edouard Cornet 1, 3 , Gandhi Damaj 1, 5 , Brigitte Sola 1 , Fabrice Jardin 2, 4 and Xavier Troussard 1, 3, 5 1 Normandie Univ, INSERM U1245, Université de Caen, Caen, France 2 Normandie Univ, INSERM U1245, Université de Rouen, Rouen, France 3 Laboratoire d'hématologie, CHU Caen, Caen, France 4 Service d'hématologie, Centre Henri Becquerel, Rouen, France 5 Institut d'Hématologie de Basse-Normandie, CHU Caen, Caen, France Correspondence to: Xavier Troussard, email: troussard-x@chu-caen.fr Keywords: hairy cell leukemia; next-generation sequencing; gene mutation; hairy cell leukemia variant; epigenetic regulation genes Received: April 13, 2018 Accepted: May 24, 2018 Published: June 22, 2018 ABSTRACT Classical hairy cell leukemia (HCL-c) is a rare lymphoid neoplasm. BRAF V600E mutation, detected in more than 80% of the cases, is described as a driver mutation, but additional genetic abnormalities appear to be necessary for the disease progression. For cases of HCL-c harboring a wild-type BRAF gene, the differential diagnosis of the variant form of HCL (HCL-v) or splenic diffuse red pulp lymphoma (SDRPL) is complex. We selected a panel of 21 relevant genes based on a literature review of whole exome sequencing studies ( BRAF , MAP2K1 , DUSP2 , MAPK15 , ARID1A , ARID1B , EZH2 , KDM6A , CREBBP , TP53 , CDKN1B , XPO1 , KLF2 , CXCR4 , NOTH1 , NOTCH2 , MYD88 , ANXA1 , U2AF1 , BCOR , and ABCA8 ). We analyzed 20 HCL-c and 4 HCL-v patients. The analysis of diagnostic samples mutations in BRAF ( n = 18), KLF2 ( n = 4), MAP2K1 ( n = 3), KDM6A ( n = 2), CDKN1B ( n = 2), ARID1A ( n = 2), CREBBP ( n = 2) NOTCH1 ( n = 1) and ARID1B ( n = 1). BRAF V600E was found in 90% (18/20) of HCL-c patients. In HCL-c patients with BRAF V600E , other mutations were found in 33% (6/18) of cases. All 4 HCL-v patients had mutations in epigenetic regulatory genes: KDM6A ( n = 2), CREBBP ( n = 1) or ARID1A ( n = 1). The analysis of sequential samples (at diagnosis and relapse) from 5 patients (2 HCL-c and 3 HCL-v), showed the presence of 2 new subclonal mutations ( BCOR E1430X and XPO1 E571K ) in one patient and variations of the mutated allele frequency in 2 other cases. In the HCL-v disease, we described new mutations targeting KDM6A that encode a lysine demethylase protein. This opens new perspectives for personalized medicine for this group of patients.