Contributions
Abstract: S865
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 16:45 - 17:00
Location: Room A4
Background
The overall prognosis of adults with B-cell acute lymphoblastic leukaemia (ALL) remains worse than that of children. One of the bottlenecks leading to the poor outcome of adults is that molecular analyses of risk cohorts in adult B-cell ALL has lagged behind progress in pediatric B-cell ALL.
Aims
Interrogate the genomic landscape of adult B-cell ALL and variants associating with leukaemogenesis and prognosis.
Methods
226 consecutive, newly-diagnosed adults with B-cell ALL seen in Peking University People’s Hospital between April, 2007 and December, 2015 were enrolled in the study. Whole-genome sequencing was performed for 8 paired samples (at diagnosis and at complete remission), whole-exome sequencing for 13 paired samples and target DNA sequencing for 210 samples including 88 paired samples. For validation, 5 paired samples were sequenced both by whole-exome and target DNA sequencing. Clonal evolution of 7 paired samples (at diagnosis and at relapse) was detected by whole-exome sequencing.
Results
We identified 2285 mutations in 791 genes (median, 11 mutations per subject) with ≥2 mutations identified in 190 subjects (84%; 95% confidence interval [CI], 79, 89%). KMT2D, also termed MLL2, represented the most frequent significantly mutated gene in our cohort (N=31; 14% [9, 19%]). We also found 4 new mutated genes, PRB2 (N=13; 6% [3, 9%]), NBPF10 (N=12; 5% [2, 8%]), TSFM (N=8; 4% [1, 7%]) and DIAPH1 (N=8; 4% [1, 7%]). 7 DIAPH1 mutated subjects with remission were matched by 56 controls according to age (<35y vs. ≥35y), t(9;22)/BCR-ABL (+ vs. -) and time to CR1 (≤33 d vs. >33d) to compare CIRs and RFSs. DIAPH1 mutation had a significantly higher CIR vs. those without a mutation (P=<0.001; Figure 1a) and worse RFS (P=<0.001; Figure 1b). In multivariate analyses DIAPH1 mutation was independently-associated with CIR (hazard ratio [HR]=4.6 [1.7, 12.7], P=0.004) and RFS (HR=4.5 [1.6, 12.6], P=0.004). Besides, 90% of the samples showed 14q32.33 loss, validating by a long non-coding RNA, KIAA0125 in this area. Mutation burden (40% VAF as a watershed) showed more importance in B-ALL development and patient survival than mutation itself. KMT2D mutation with VAF≥40% indicated higher relapse risk compared with the wild-type ones(Figure 1c,1d). Multivariate analyses also revealed that KMT2D mutation with VAF≥40% was an independent risk factor for CIR (HR=2.4 [1.3, 4.3], P=0.006) and RFS (HR=2.3 [1.2, 4.4], P=0.013). Moreover, genes with VAF ≥40% predispose them to persistence at relapse.
Conclusion
These data provide insights into the genomic landscape of adults with B-cell ALL, identify diverse mutations with 4 new mutated genes and frequent copy number loss in 14q32.33, which may highly correlate with leukaemogenesis. Besides, targeting mutations with VAF ≥40% may benefit patients as more clinically relevant. (Trial registered in the Beijing Municipal Health Bureau Registration N: 2007–1007 and the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTR-OPC-14005546]; http://www.chictr.org.cn)
Session topic: 1. Acute lymphoblastic leukemia – Biology & Translational Research
Keyword(s): adult, B cell acute lymphoblastic leukemia, Genomics, Molecular markers
Abstract: S865
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 16:45 - 17:00
Location: Room A4
Background
The overall prognosis of adults with B-cell acute lymphoblastic leukaemia (ALL) remains worse than that of children. One of the bottlenecks leading to the poor outcome of adults is that molecular analyses of risk cohorts in adult B-cell ALL has lagged behind progress in pediatric B-cell ALL.
Aims
Interrogate the genomic landscape of adult B-cell ALL and variants associating with leukaemogenesis and prognosis.
Methods
226 consecutive, newly-diagnosed adults with B-cell ALL seen in Peking University People’s Hospital between April, 2007 and December, 2015 were enrolled in the study. Whole-genome sequencing was performed for 8 paired samples (at diagnosis and at complete remission), whole-exome sequencing for 13 paired samples and target DNA sequencing for 210 samples including 88 paired samples. For validation, 5 paired samples were sequenced both by whole-exome and target DNA sequencing. Clonal evolution of 7 paired samples (at diagnosis and at relapse) was detected by whole-exome sequencing.
Results
We identified 2285 mutations in 791 genes (median, 11 mutations per subject) with ≥2 mutations identified in 190 subjects (84%; 95% confidence interval [CI], 79, 89%). KMT2D, also termed MLL2, represented the most frequent significantly mutated gene in our cohort (N=31; 14% [9, 19%]). We also found 4 new mutated genes, PRB2 (N=13; 6% [3, 9%]), NBPF10 (N=12; 5% [2, 8%]), TSFM (N=8; 4% [1, 7%]) and DIAPH1 (N=8; 4% [1, 7%]). 7 DIAPH1 mutated subjects with remission were matched by 56 controls according to age (<35y vs. ≥35y), t(9;22)/BCR-ABL (+ vs. -) and time to CR1 (≤33 d vs. >33d) to compare CIRs and RFSs. DIAPH1 mutation had a significantly higher CIR vs. those without a mutation (P=<0.001; Figure 1a) and worse RFS (P=<0.001; Figure 1b). In multivariate analyses DIAPH1 mutation was independently-associated with CIR (hazard ratio [HR]=4.6 [1.7, 12.7], P=0.004) and RFS (HR=4.5 [1.6, 12.6], P=0.004). Besides, 90% of the samples showed 14q32.33 loss, validating by a long non-coding RNA, KIAA0125 in this area. Mutation burden (40% VAF as a watershed) showed more importance in B-ALL development and patient survival than mutation itself. KMT2D mutation with VAF≥40% indicated higher relapse risk compared with the wild-type ones(Figure 1c,1d). Multivariate analyses also revealed that KMT2D mutation with VAF≥40% was an independent risk factor for CIR (HR=2.4 [1.3, 4.3], P=0.006) and RFS (HR=2.3 [1.2, 4.4], P=0.013). Moreover, genes with VAF ≥40% predispose them to persistence at relapse.
Conclusion
These data provide insights into the genomic landscape of adults with B-cell ALL, identify diverse mutations with 4 new mutated genes and frequent copy number loss in 14q32.33, which may highly correlate with leukaemogenesis. Besides, targeting mutations with VAF ≥40% may benefit patients as more clinically relevant. (Trial registered in the Beijing Municipal Health Bureau Registration N: 2007–1007 and the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTR-OPC-14005546]; http://www.chictr.org.cn)
Session topic: 1. Acute lymphoblastic leukemia – Biology & Translational Research
Keyword(s): adult, B cell acute lymphoblastic leukemia, Genomics, Molecular markers