PB1885 GENOMIC CHARACTERIZATION OF CHRONIC LYMPHOCYTIC LEUKEMIA AND MULTIPLE MYELOMA: ROLE OF ARRAY COMPARATIVE GENOMIC HYBRIDIZATION (ACGH)
Authors: Nascimento T. , Adão D. , Oliveira A. , Pires L.M. , Alves R.S. , Jorge J. , Ribeiro I.P. , Duarte S. , Carda J.P. , Roque A. , Paiva A. , Pereira A. , Azevedo J. , Ribeiro M.L. , Barbosa de Melo J. , Gonçalves A. , Carreira I.M. , Sarmento‐Ribeiro A.B. 
Published: June 2019

Background:Genomic abnormalities play a key role in the biological properties and clinical behavior of hematological malignancies, namely in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). These diseases have particularly benefited from gene expression profiling and genomic characterization, which improved diagnosis, prognosis and therapy response prediction. Conventional cytogenetics (CC) and fluorescence in situ hybridization (FISH) play a crucial role in the detection of cytogenetics abnormalities in these hematologic malignancies. However, these techniques had limitations, while CC requires proliferating cells and FISH is a targeted technique, underestimating the extent of chromosomal changes. Array comparative genomic hybridization (aCGH) had facilitated diagnosis and gene discovery with the ability to perform genome‐wide research and in high concordance with the cytogenetic and FISH results. These features facilitate the detection of clinically relevant findings that would be missed by other techniques.Aims:Therefore, the aim of this study was to screen and identify new genomic events in CLL and MM patients by aCGH in order to identify new potential prognostic biomarkers.Methods:To this end, 19 CLL patients at diagnosis [9 females/10 males; 74 years (50‐90); Binet stage (n = 18): A (n = 15, 83%) e C (n = 3, 17%)], 1 monoclonal B lymphocytosis (MBL; male; 81 years) and 10 MM patients (4 females/6 males; 74 years (54‐90) were analyzed by aCGH. Genomic DNA was obtained from peripheral blood mononuclear cells of CLL patients and from plasma cells (CD138+ isolated by MACS) from bone marrow samples of MM patients. The results were analyzed statistically considering a significance level of 95% (p < 0.05).Results:Results show that CLL patients have a median of 8 copy number variants (CNVs) per patient, ranging from 3 to 11, and MM patients have a median of 10 CNVs/patient, ranging from 1 to 23. Among the 137 CNVs detected in CLL patients, 65% were losses (n = 87) and 35% gains (n = 47), with an average of 4.4 losses/CLL case and 2.4 gains/CLL case. The patient with MBL had 10 CNVs (4 losses and 6 gains). In MM patients were detected 107 CNVs, 37% were losses (n = 40) and 63% gains (n = 67) with an average of 4.0 losses/MM case and 6.7 gains/MM case. These CNVs have several sizes ranging from 50 bp to 130 Mb in CLL and from 8.6 Kb to 131 Mb in MM, encompassing genes with malignant potential. We found several recurrent CNVs in CLL patients: 7 del (14q) (35%); 7 del(13q) (35%), 6 tris 12 (30%), 2 del(11q) (10%), 5 del(6q) (25%), 3 del(8p) (15%), 2 dup(8q) (10%) and 2 dup(2p) (5%). We also found 2 del(9p21.3) (10.0%), a rare abnormality in CLL. Additionally, all high‐risk patients (Binet C) have a del(14q) but these CNVs were less frequent in low‐risk CLL patients (Binet A: 20%, n = 3, p = 0,007). In MM patients the following recurrent CNVs were found: 7 del(13q) (70%), 5 dup(1q) (50%), 4 tris 9 (40%) and 4 del(14q) (40%). Events involving X chromosome, including monosomy and trisomy, were detected in 4 MM patients (40%). Interestingly, 6 out of 7 patients with del(13q) present a minimal deleted region (13q14.11‐q14.3) established previously by other groups.Summary/Conclusion:This study suggests that MM patients have a higher genomic complexity than CLL patients and that aCGH have potential to identify new prognostic markers in these pathologies.