Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL. This work shows that treatments used for acute myeloid leukaemia and targeted therapies could be used for early T-cell precursor acute lymphoblastic leukaemia. The early T-cell precursor (ETP) subtype of childhood acute lymphoblastic leukaemia (ALL) has a poor prognosis when treated with standard chemotherapy. Whole genome sequencing is used here to gain insights into the genetic basis of the condition. The results reveal a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling, lesions that disrupt haemopoiesis (many of which arise from chromosomal rearrangements that generate novel chimeric in-frame fusion genes), and inactivating mutations in histone modifying genes. This mutation pattern resembles that of myeloid malignancies, suggesting that myeloid-directed therapies such as high-dose cytarabine, or targeted therapies that inhibit cytokine receptor and JAK signalling, might be effective in ETP ALL.
Vincristine (VCR) is an important component of curative chemotherapy for many childhood cancers. Its main side effect is VCR-induced peripheral neuropathy (VIPN), a dose limiting toxicity. Some children are more susceptible to VIPN, which is at least partially dependent on genetic factors and pharmacokinetics (PK). In this study, we identify and replicate genetic variants associated with VCR PK and VIPN. Patient samples from a randomized clinical trial studying the effect of administration duration of VCR on VIPN in 90 patients were used. PK sampling was conducted on between one and five occasions at multiple time points. A linear two-compartment model with first-order elimination was used, and targeted next-generation DNA sequencing was performed. Genotype-trait associations were analyzed using mixed-effect models or logistic regression analysis for repeated measures, or Poisson regression analysis in which the highest VIPN score per patient was included. Nine single-nucleotide polymorphisms (SNPs) in seven genes (NDRG1, GARS, FIG4, FGD4, SEPTIN9, CEP72, and ETAA1) were associated with VIPN. Furthermore, three SNPs in three genes (MTNR1B, RAB7A and SNU13) were associated with PK of VCR. In conclusion, PK of VCR and VIPN are influenced by SNPs; upfront identification of those that lead to an altered susceptibility to VIPN or VCR exposure could help individualize VCR treatment.
Recent genome-wide screens have identified genetic variations in ARID5B associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). We sought to determine the contribution of ARID5B single nucleotide polymorphisms (SNPs) to racial disparities in ALL susceptibility and treatment outcome.We compared the association between ARID5B SNP genotype and ALL susceptibility in whites (> 95% European genetic ancestry; 978 cases and 1,046 controls) versus in Hispanics (> 10% Native American ancestry; 330 cases and 541 controls). We determined the relationships between ARID5B SNP genotype and ALL relapse risk in 1,605 children treated on the Children's Oncology Group (COG) P9904/9905 clinical trials.Among 49 ARID5B SNPs interrogated, 10 were significantly associated with ALL susceptibility in both whites and Hispanics (P < .05), with risk alleles consistently more frequent in Hispanics than in whites. rs10821936 exhibited the most significant association in both races (P = 8.4 × 10(-20) in whites; P = 1 × 10(-6) in Hispanics), and genotype at this SNP was highly correlated with local Native American genetic ancestry (P = 1.8 × 10(-8)). Multivariate analyses in Hispanics identified an additional SNP associated with ALL susceptibility independent of rs10821936. Eight ARID5B SNPs were associated with both ALL susceptibility and relapse hazard; the alleles related to higher ALL incidence were always linked to poorer treatment outcome and were more frequent in Hispanics.ARID5B polymorphisms are important determinants of childhood ALL susceptibility and treatment outcome, and they contribute to racial disparities in this disease.
The methodological advancement in microarray data analysis on the basis of false discovery rate (FDR) control, such as the q-value plots, allows the investigator to examine the FDR from several perspectives. However, when FDR control at the “customary" levels 0.01, 0.05, or 0.1 does not provide fruitful findings, there is little guidance for making the trade off between the significance threshold and the FDR level by sound statistical or biological considerations. Thus, meaningful statistical significance criteria that complement the existing FDR methods for large-scale multiple tests are desirable. Three statistical significance criteria, the profile information criterion, the total error proportion, and the guide-gene driven selection, are developed in this research. The first two are general significance threshold criteria for large-scale multiple tests; the profile information criterion is related to the recent theoretical studies of the connection between FDR control and minimax estimation, and the total error proportion is closely related to the asymptotic properties of FDR control in terms of the total error risk. The guide-gene driven selection is an approach to combining statistical significance and the existing biological knowledge of the study at hand. Error properties of these criteria are investigated theoretically and by simulation. The proposed methods are illustrated and compared using an example of genomic screening for novel Arf gene targets. Operating characteristics of q-value and the proposed significance threshold criteria are investigated and compared in a simulation study that employs a model mimicking a gene regulatory pathway. A guideline for using these criteria is provided. Splus/R code is available from the corresponding author upon request.
Abstract Introduction: Prognostic biomarkers in childhood acute lymphoblastic leukemia (ALL) are vital for risk-stratification and intensifying therapy for children at high risk for remission induction failure or relapse. Copy number alterations in genes such as IKZF1 and VPREB1 have been shown to correlate with poor outcome in ALL, highlighting genetic alterations as prognostic markers (NEJM 360:470, 2009, Leukemia 28(1):216-20, 2014). A second focal deletion in chromosome 22q11.22, 200 kilobases (Kb) in length, occurs more frequently and in the same IGLL region as VPREB1 and is distinct from deletions associated with physiologic IGLL rearrangement. We further investigated this novel genomic lesion, 22q11.22, and the prevalence of co-occurrence with IKZF1. Methods: 22q11.22 deletions were characterized in a compiled childhood ALL cohort (N=832) and correlated with available clinical outcome using multiple previously published studies (Clinical outcome total N=730; Utah Cohort [N=56], TARGET P9906 cohort [N=215], St. Jude Children's Research Hospital cohort [SJCRH, N=236], Children’s Hospital of Philadelphia cohort [CHOP, N=160], and Down Syndrome cohort [DS, N=63]). Microarray data was analyzed (Utah = Molecular Inversion Probe 330K [Affymetrix]; TARGET = SNP 500K [Affymetrix]; SJCRH = SNP 500K/6.0 [Affymetrix], CHOP = 850K, 610K, and Omni Quadv1 [Illumina], DS = SNP 500K, MIP 330K [Affymetrix]) by Nexus Copy Number (BioDiscovery, Inc.). Results: ALL patients that harbored copy number deletion 22q11.22 were present in about 30-45% of each cohort: Utah = 42.8%, TARGET = 29%, SJCRH = 40%, CHOP = 34%, DS = 46.7%. The majority of deletions, 93%, had a common recurring region just under 12 Kb in length. The 12 Kb deleted segment encodes no known genes. Patients that harbored a combined deletion in both IKZF1 and 22q11.22 (IKZF1+22q) were present in about 10-15% of each cohort: Utah = 12.5%, TARGET = 18%, SJCRH = 8.4%, CHOP = 6.3%, DS = 14.4%. IKZF1+22q conferred worse event-free survival (N=730, P=0.0062) compared to those with only IKZF1 deletions and worse overall survival (N=507, P=0.0365). Additionally, those patients with IKZF1+22q losses had a median decrease in event-free survival compared to those patients with neither deletion (normal cases): TARGET (high risk cohort) = 0.63 years, P=<0.0001, SJCRH (standard, low risk cohort) = 10 years, P=<0.0001, DS = 2.3 years, P=<0.0001. Conclusion: We present further evidence that non-physiological deletions within the IGLL locus is associated with worse outcome in pediatric ALL and combined with IKZF1, these double deletions identify a population of patients with very poor outcomes. These combined alterations may be useful to identify patients in the future for high risk stratification and further work is now needed to understand the mechanism and biological consequence of this common loss at 22q11.22 in childhood ALL. Citation Format: Julia A. Meyer, Clint C. Mason, Luke Maese, Deqing Pei, Cheng Cheng, Ching-Hon Pui, Mel Greaves, Richard Aplenc, Charles G. Mulligan, Elizabeth Raetz, Rodney R. Miles, Karen R. Rabin, Joshua D. Schiffman. Focal 22q11.22 deletions combined with IKZF1 alterations are associated with worse clinical outcome in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4884. doi:10.1158/1538-7445.AM2017-4884
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