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

Elsa Maitre (1) , Philippe Bertrand (1) , Catherine Maingonnat (1) , Pierre-Julien Viailly (1) , Margaux Wiber (2) , Dina Naguib (2) , Véronique Salaün (2) , Edouard Cornet (1) , Gandhi Damaj (3, 2) , Brigitte Sola (1) , Fabrice Jardin (1, 4) , Xavier Troussard (5, 2, 1)

1 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
2 CHU Caen
3 IHBN - Institut d'Hématologie de Basse-Normandie
4 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
5 Registre des hémopathies malignes de Basse-Normandie [CHU Caen]

Classical hairy cell leukemia (HCL-c) is a rare lymphoid neoplasm. BRAFV600E 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). BRAFV600E was found in 90% (18/20) of HCL-c patients. In HCL-c patients with BRAFV600E , 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 (BCORE1430X and XPO1E571K ) 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.

Mots clés: epigenetic regulation genes; gene mutation; hairy cell leukemia; hairy cell leukemia variant; next-generation sequencing

Domaines: Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Hématologie

Elsa Maitre, Philippe Bertrand, Catherine Maingonnat, Pierre-Julien Viailly, Margaux Wiber, et al.. New generation sequencing of targeted genes in the classical and the variant form of hairy cell leukemia highlights mutations in epigenetic regulation genes. Oncotarget, 2018, 9 (48), pp.28866-28876. ⟨10.18632/oncotarget.25601⟩. ⟨hal-01929708⟩