PMID- 27633522 OWN - NLM STAT- MEDLINE DCOM- 20171201 LR - 20181113 IS - 1756-8722 (Electronic) IS - 1756-8722 (Linking) VI - 9 IP - 1 DP - 2016 Sep 15 TI - Extensive next-generation sequencing analysis in chronic lymphocytic leukemia at diagnosis: clinical and biological correlations. PG - 88 LID - 10.1186/s13045-016-0320-z [doi] LID - 88 AB - BACKGROUND: In chronic lymphocytic leukemia (CLL), next-generation sequencing (NGS) analysis represents a sensitive, reproducible, and resource-efficient technique for routine screening of gene mutations. METHODS: We performed an extensive biologic characterization of newly diagnosed CLL, including NGS analysis of 20 genes frequently mutated in CLL and karyotype analysis to assess whether NGS and karyotype results could be of clinical relevance in the refinement of prognosis and assessment of risk of progression. The genomic DNA from peripheral blood samples of 200 consecutive CLL patients was analyzed using Ion Torrent Personal Genome Machine, a NGS platform that uses semiconductor sequencing technology. Karyotype analysis was performed using efficient mitogens. RESULTS: Mutations were detected in 42.0 % of cases with 42.8 % of mutated patients presenting 2 or more mutations. The presence of mutations by NGS was associated with unmutated IGHV gene (p = 0.009), CD38 positivity (p = 0.010), risk stratification by fluorescence in situ hybridization (FISH) (p < 0.001), and the complex karyotype (p = 0.003). A high risk as assessed by FISH analysis was associated with mutations affecting TP53 (p = 0.012), BIRC3 (p = 0.003), and FBXW7 (p = 0.003) while the complex karyotype was significantly associated with TP53, ATM, and MYD88 mutations (p = 0.003, 0.018, and 0.001, respectively). By multivariate analysis, the multi-hit profile (>/=2 mutations by NGS) was independently associated with a shorter time to first treatment (p = 0.004) along with TP53 disruption (p = 0.040), IGHV unmutated status (p < 0.001), and advanced stage (p < 0.001). Advanced stage (p = 0.010), TP53 disruption (p < 0.001), IGHV unmutated status (p = 0.020), and the complex karyotype (p = 0.007) were independently associated with a shorter overall survival. CONCLUSIONS: At diagnosis, an extensive biologic characterization including NGS and karyotype analyses using novel mitogens may offer new perspectives for a better refinement of risk stratification that could be of help in the clinical management of CLL patients. FAU - Rigolin, Gian Matteo AU - Rigolin GM AUID- ORCID: 0000-0002-8370-5190 AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. rglgmt@unife.it. FAU - Saccenti, Elena AU - Saccenti E AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Bassi, Cristian AU - Bassi C AD - Department of Morphology, Surgery and Experimental Medicine, and "Laboratorio per le Tecnologie delle Terapie Avanzate" (LTTA), University of Ferrara, Ferrara, Italy. FAU - Lupini, Laura AU - Lupini L AD - Department of Morphology, Surgery and Experimental Medicine, and "Laboratorio per le Tecnologie delle Terapie Avanzate" (LTTA), University of Ferrara, Ferrara, Italy. FAU - Quaglia, Francesca Maria AU - Quaglia FM AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Cavallari, Maurizio AU - Cavallari M AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Martinelli, Sara AU - Martinelli S AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Formigaro, Luca AU - Formigaro L AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Lista, Enrico AU - Lista E AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Bardi, Maria Antonella AU - Bardi MA AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Volta, Eleonora AU - Volta E AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Tammiso, Elisa AU - Tammiso E AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Melandri, Aurora AU - Melandri A AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Urso, Antonio AU - Urso A AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Cavazzini, Francesco AU - Cavazzini F AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. FAU - Negrini, Massimo AU - Negrini M AD - Department of Morphology, Surgery and Experimental Medicine, and "Laboratorio per le Tecnologie delle Terapie Avanzate" (LTTA), University of Ferrara, Ferrara, Italy. FAU - Cuneo, Antonio AU - Cuneo A AD - Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Via Aldo Moro, 8, 44124, Ferrara, Cona, Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160915 PL - England TA - J Hematol Oncol JT - Journal of hematology & oncology JID - 101468937 RN - 0 (F-Box-WD Repeat-Containing Protein 7) RN - 0 (FBXW7 protein, human) RN - 0 (MYD88 protein, human) RN - 0 (Myeloid Differentiation Factor 88) RN - 0 (Tumor Suppressor Protein p53) RN - EC 2.3.2.27 (BIRC3 protein, human) RN - EC 2.3.2.27 (Baculoviral IAP Repeat-Containing 3 Protein) RN - EC 2.7.11.1 (ATM protein, human) RN - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins) SB - IM EIN - J Hematol Oncol. 2016 Sep 30;9(1):103. PMID: 27716358 MH - Adult MH - Aged MH - Aged, 80 and over MH - Ataxia Telangiectasia Mutated Proteins/genetics MH - Baculoviral IAP Repeat-Containing 3 Protein/genetics MH - DNA Mutational Analysis MH - F-Box-WD Repeat-Containing Protein 7/genetics MH - Female MH - *High-Throughput Nucleotide Sequencing MH - Humans MH - In Situ Hybridization, Fluorescence MH - Karyotyping MH - Leukemia, Lymphocytic, Chronic, B-Cell/*diagnosis/*genetics MH - Male MH - Middle Aged MH - Myeloid Differentiation Factor 88/genetics MH - Risk Assessment/*methods MH - Tumor Suppressor Protein p53/genetics PMC - PMC5025606 OTO - NOTNLM OT - Chronic lymphocytic leukemia OT - Complex karyotype OT - Gene mutation analysis OT - Next-generation sequencing OT - Prognosis EDAT- 2016/09/17 06:00 MHDA- 2017/12/02 06:00 PMCR- 2016/09/15 CRDT- 2016/09/17 06:00 PHST- 2016/08/19 00:00 [received] PHST- 2016/09/06 00:00 [accepted] PHST- 2016/09/17 06:00 [entrez] PHST- 2016/09/17 06:00 [pubmed] PHST- 2017/12/02 06:00 [medline] PHST- 2016/09/15 00:00 [pmc-release] AID - 10.1186/s13045-016-0320-z [pii] AID - 320 [pii] AID - 10.1186/s13045-016-0320-z [doi] PST - epublish SO - J Hematol Oncol. 2016 Sep 15;9(1):88. doi: 10.1186/s13045-016-0320-z.