Introduction. Genome-wide profiling of B/T-ALL identified many novel somatic alterations, several of which have clear implications for risk stratification or future therapeutic targeting. However, most of the studies focused on children and therefore a deep molecular characterization of adults is still challenging, especially for those cases lacking recurrent fusion genes. Subjects-Methods. In order to shed light on this ALL subgroup, until now we retrospectively analyzed 28 newly diagnosed BC-ALL subjects (19 males/9 females; median age 41.5 years; negative for known fusion genes). Karyotype was normal in 10/28 (36%), showed abnormalities in 5/28 (18%) and failed or was not available in 13/28 (46%) cases. Overall survival rate was very poor with a median of 14 months (range, 1-75). We analyzed copy number alterations (CNA) of IKZF1, CDKN2A/B, PAX5, EBF1, ETV6, BTG1, RB1, and genes within PAR1: CRLF2, CSF2RA, IL3RA by the SALSA MLPA kit P335 IKZF1 (MRC Holland). In addition, mutation status was assessed for TP53, CRLF2, JAK2, LEF1, PAX5 and IL7R by next generation sequencing (NGS) with GS Junior (Roche Applied Science; IRON-II study oligonucleotide primer plates). Moreover, SNP arrays analysis was performed in 57% of cases to more fully assess genomic complexity. Results. Overall 76% of subjects showed an abnormality of at least one of the analyzed genes: 7 (25%) had one, 4 (14%) had two, 6 (21%) had three, 6 (21%) had four or more alterations. In subjects showing no abnormalities, SNP arrays analysis revealed amplification of chromosome 1q in 2/6 (33%). Deletions of CDKN2A/B were the most frequent (39%) and in 73%, they occurred together with other abnormalities, suggesting that multiple events are needed to induce the full leukemia phenotype. Other common CNA included: deletions of IKZF1 (25%), ETV6 (25%),AX5 (14%), EBF1 (11%), PAR1 region (11%) and RB1 (7%). NGS showed mutations of TP53 in 18% of cases (W147*, V172L/G, G245C, Del244-246, D259Y) while JAK2 and CRLF2 were mutated in 7% (R683S/G) and 4% (F232C), respectively. Importantly, subjects with no abnormalities showed better survival rates compared to those with one or more molecular alterations (p<0.01). Conclusions: BC-ALL lacking recurring fusion genes is a highly heterogeneous and complex disease. Current diagnostic procedures are in need of revision to improve risk assessment and to guide therapeutic decisions. Supported: ELN, AIL, AIRC, Fondazione del Monte, PRIN 2011, NGS-PTL project.
DEEP MOLECULAR CHARACTERIZATION OF ADULT B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (BC-ALL) NEGATIVE FOR RECURRENT FUSION GENES REVEALS A HIGH COMPLEX GENETIC HETEROGENEITY INFLUENCING PROGNOSIS
IACOBUCCI, ILARIA;Ferrari, A;PERRICONE, MARGHERITA;Papayannidis, C;ZUNTINI, ROBERTA;ROBUSTELLI, VALENTINA;GHELLI LUSERNA DI RORÀ, ANDREA;LONETTI, ANNALISA;GUADAGNUOLO, VIVIANA;Parisi, S;SARTOR, CHIARA;CATTINA, FEDERICA;
2013
Abstract
Introduction. Genome-wide profiling of B/T-ALL identified many novel somatic alterations, several of which have clear implications for risk stratification or future therapeutic targeting. However, most of the studies focused on children and therefore a deep molecular characterization of adults is still challenging, especially for those cases lacking recurrent fusion genes. Subjects-Methods. In order to shed light on this ALL subgroup, until now we retrospectively analyzed 28 newly diagnosed BC-ALL subjects (19 males/9 females; median age 41.5 years; negative for known fusion genes). Karyotype was normal in 10/28 (36%), showed abnormalities in 5/28 (18%) and failed or was not available in 13/28 (46%) cases. Overall survival rate was very poor with a median of 14 months (range, 1-75). We analyzed copy number alterations (CNA) of IKZF1, CDKN2A/B, PAX5, EBF1, ETV6, BTG1, RB1, and genes within PAR1: CRLF2, CSF2RA, IL3RA by the SALSA MLPA kit P335 IKZF1 (MRC Holland). In addition, mutation status was assessed for TP53, CRLF2, JAK2, LEF1, PAX5 and IL7R by next generation sequencing (NGS) with GS Junior (Roche Applied Science; IRON-II study oligonucleotide primer plates). Moreover, SNP arrays analysis was performed in 57% of cases to more fully assess genomic complexity. Results. Overall 76% of subjects showed an abnormality of at least one of the analyzed genes: 7 (25%) had one, 4 (14%) had two, 6 (21%) had three, 6 (21%) had four or more alterations. In subjects showing no abnormalities, SNP arrays analysis revealed amplification of chromosome 1q in 2/6 (33%). Deletions of CDKN2A/B were the most frequent (39%) and in 73%, they occurred together with other abnormalities, suggesting that multiple events are needed to induce the full leukemia phenotype. Other common CNA included: deletions of IKZF1 (25%), ETV6 (25%),AX5 (14%), EBF1 (11%), PAR1 region (11%) and RB1 (7%). NGS showed mutations of TP53 in 18% of cases (W147*, V172L/G, G245C, Del244-246, D259Y) while JAK2 and CRLF2 were mutated in 7% (R683S/G) and 4% (F232C), respectively. Importantly, subjects with no abnormalities showed better survival rates compared to those with one or more molecular alterations (p<0.01). Conclusions: BC-ALL lacking recurring fusion genes is a highly heterogeneous and complex disease. Current diagnostic procedures are in need of revision to improve risk assessment and to guide therapeutic decisions. Supported: ELN, AIL, AIRC, Fondazione del Monte, PRIN 2011, NGS-PTL project.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
