scholarly journals Evaluation of DNA Methylation at Birth in Monozygotic Twin Pairs Discordant for Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2278-2278
Author(s):  
Eric M. Nickels ◽  
Shaobo Li ◽  
Katti Arroyo ◽  
Swe Swe Myint ◽  
Adam J. de Smith ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Logistic Regression ◽  
Lymphoblastic Leukemia ◽  
Conditional Logistic Regression ◽  
Monozygotic Twin ◽  
Control Measures ◽  
P Value ◽  
Conditional Logistic Regression Model ◽  
P Values ◽  
Pediatric All

Abstract Background: Aberrant patterns of DNA methylation constitute a key feature of pediatric acute lymphoblastic leukemia (ALL) at diagnosis, however its role as a predisposing or early contributor to the development of ALL remains unknown. We employed a discordant monozygotic twin model to identify epigenetic variation associated with future development of pediatric ALL through evaluation of DNA methylation at birth. Methods: Twin pairs discordant for the development of pediatric ALL were identified using linked data from the California Cancer Registry and California Birth Statistical Master File spanning from 1989 to 2015. Archived dried neonatal blood spots were obtained from 86 same-gender twin pairs with available materials from the California Biobank Program. Following isolation of genomic DNA from DBS samples, monozygosity was confirmed in 43 of 86 twin pairs through an identity-by-descent analysis from a genome-wide SNP-array. Epigenome-wide DNA methylation assessment of the 43 discordant monozygotic twin pairs was conducted using the Illumina Infinium MethylationEPIC BeadChip kit (Illumina, San Diego, CA, USA). Data preprocessing and quality control measures were conducted in R, using SeSAMe for data normalization. Two twin pairs were omitted due to failure to pass quality control measures. Within-pair analysis was conducted through identification of array probes with absolute differences in methylation beta values greater than 15% between case and control siblings of a twin pair unit. Differentially methylated probes (DMP) were identified using a conditional logistic regression model accounting for array-specific variation, nucleated cell proportions, and appropriate control for the paired nature of the dataset. Differentially methylated regions (DMR) were defined by regional correlation of p-values from the conditional logistic regression model. Gene set enrichment analysis was conducted on significant probes identified through the within pair and regression analysis. Results: The discordant twin cohort (n = 41 pairs) included 24 female and 17 male pairs. Median gestational age was 258 days, ranging from 184 to 306 days. Age of diagnosis in the case twin ranged from <1 to 23 years (median = 5). There was no significant association between birthweight and case status (paired Wilcoxon signed rank test p = 0.22). No significant differences in nucleated cell proportions were identified in deconvolution analysis. Within-pair analysis identified a total of 18,001 probes with absolute methylation variation greater than 15% across the 41 twin pairs, with 3,984 recurrently variable across more than one pair. Gene ontology analysis of these recurrently variable sites revealed an enrichment of immune-related processes in 7 of the top 15 terms with nominal p-value <0.05, though no terms were significant after correction for multiple comparisons. Conditional logistic regression was conducted on 37 twin pairs, with T-cell cases (n=4) omitted to improve data resolution. This resulted in 240 significant DMPs with p-values below an FDR threshold of 0.05. Of these significant probes, 20 associate with genes previously reported to have altered DNA methylation in ALL at diagnosis. Regional analysis identified 10 significant DMRs with adjusted p-values below 0.05, with the top association encompassing a 454bp region on chromosome 6 located near TRIM39-RPP21 (adjusted p-value 2.39e-05). Notably, conditional regression analysis revealed a significant negative bias in coefficients (409,812 of 710,010 probes, binomial exact test p <2.2e-16), indicating a global tendency toward hypomethylation in cases compared to unaffected siblings (Figure 1). The strength of this bias was greater in probes associated with open sea regions compared to those in island regions, as well as promoter-associated probes. Conclusions: This novel analysis of DNA methylation at birth in ALL-discordant monozygotic twins identified sites of differential methylation associated with immune regulation. In addition, these results provide evidence of an association between global DNA hypomethylation and future development of ALL in one member of a genetically identical twin pair. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Aberrant DNA Methylation Patterns in Peripheral Blood Are Detectable Years before the Diagnosis of Mature B Cell Neoplasms

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1521-1521
Author(s):  
Nicole Wong Doo ◽  
Enes Makalic ◽  
Daniel Schmidt ◽  
Jihoon E Joo ◽  
Chol-Hee Jung ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Logistic Regression ◽  
Cohort Study ◽  
B Cell ◽  
Peripheral Blood ◽  
Conditional Logistic Regression ◽  
P Value ◽  
Bonferroni Adjustment ◽  
Aberrant Dna Methylation ◽  
Methylation Patterns

Abstract Background Aberrant DNA methylation is a feature of mature B cell neoplasms (MBCN) however it is not clear whether this is an early or late event in the development of MBCN. We have previously reported that aberrant global methylation patterns are detectable in peripheral blood sampled years prior to diagnosis and now hypothesize that abnormal methylation at specific genomic regions precedes the diagnosis of MBCN. Methods: In our prospective cohort study peripheral blood was collected from healthy participants in the Melbourne Collaborative Cohort Study, (41,514 adult volunteers, recruited from 1990-94). Blood was stored as either dried blood spots, mononuclear cells or buffy coat. New cases of MBCN (including low grade non Hodgkin lymphoma [NHL], high grade NHL, chronic lymphocytic leukaemia and multiple myeloma) diagnosed during follow up until December 2011 were identified by cancer registry linkage. Cases were matched to controls at a 1:1 ratio based on age, gender, ethnicity and DNA source. Genome-wide DNA methylation was measured using the Infinium®HumanMethylation450 BeadChip and M values were derived after background correction, normalization and probe bias correction methods. Differentially methylated probes (DMPs) were identified by conditional logistic regression using case-control status as the outcome to compute odds ratios and p values for the association between methylation difference and occurrence of MBCN. Bonferroni adjustment was used for multiple testing correction. Adjusted conditional logistic regression models were created to control for the white blood cell (WBC) content of peripheral blood samples. Differentially methylated regions (DMRs) were identified using the DMRcate package. DMPs and DMRs were cross-checked against genes associated with MBCN pathogenesis by a review of current literature. Results We identified 438 cases of MBCN, with a median time between blood collection and MBCN diagnosis of 10.6 years. Following Bonferroni p value adjustment, there were 1,215 DMPs of which 81 were more methylated in cases compared to controls. There were 74 promoter-associated DMPs, with increased methylation in: HOXA9 (cg07778029, OR, 1.58; 95% CI, 1.36-1.83[punadj 2.4x10-9]), HOXA11 (cg05977669, OR, 1.62; 95% CI, 1.37-1.92 [punadj 2.0x10-8], cg24446586, OR, 1.57; 95% CI, 1.34-1.85 [punadj 2.4x10-8]), MYADM (cg25693289, OR, 1.64; 95% CI, 1.39-1.92 [punadj 1.59x10-9]). Decreased methylation of DMPs was noted in: ROBO1 (cg24512093, OR, 1.67; 95% CI, 1.39-1.96 [punadj 2.83x10-8]) and IKBKB (cg11283404, OR, 1.54; 95% CI, 1.32-1.82 [punadj 8.66x10-8]).Using a more relaxed p value cut-off (p < 1x10-5 before Bonferroni adjustment), we identified 10,792 DMPs with 17 probes corresponding to nine genes involved in MBCN pathogenesis: CARD11, CD79B, TNFAIP3, NR2F2, NPTX2, NOTCH1, NOTCH2, EP300 and DTX1. Adjustment for cell content did not significantly change the results. Analysis of differentially methylated regions (clusters of differentially methlyated probes) revealed 4,629 DMRs with p <1x10-7. Of these, 1,824 regions were more methylated in cases and included several genes of interest in MBCN pathogenesis (e.g. GATA3, HOXA9, HOXA11, EBF3, SOX11, SOX9). Conclusions This is the first study to report differential DNA methylation patterns detectable in the peripheral blood many years prior to MBCN diagnosis. Increased methylation of promoter-associated probes in HOXA9, HOXA11 and MYADM and decreased methylation of probes in ROBO1 and IKBKB were associated with an increased risk of developing MBCN. These findings suggest that aberrant methylation is a very early event in the pathogenesis of MBCN. Disclosures No relevant conflicts of interest to declare.

scholarly journals Assessment of obesity and hepatic late adverse effects in the Egyptian survivors of pediatric acute lymphoblastic leukemia: single center study

2017 ◽  
Vol 9 (1) ◽  
pp. e2017026 ◽  
Author(s):  
Farida El-Rashedy ◽  
Mahmoud Ahmed El-Hawy ◽  
Sally El Hefnawy ◽  
Mona Mohammed
Keyword(s):  
Hepatitis C ◽  
Acute Lymphoblastic Leukemia ◽  
Adverse Effects ◽  
Liver Enzymes ◽  
Lymphoblastic Leukemia ◽  
Overweight And Obesity ◽  
Direct Bilirubin ◽  
P Value ◽  
Late Adverse Effects ◽  
Pediatric All

BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) with current cure rates reaching 80% emphasizes the necessity to determine treatment related long-term effects. The aim of this study is to estimate the prevalence of overweight, obesity and hepatic late adverse effects in a cohort of ALL survivors treated at the Hematology and Oncology Unit, Pediatrics Department, Menoufia University, Egypt.METHODS: In this case control study, height, weight and body mass index (BMI) were assessed for 35 pediatric ALL survivors and 15 healthy children. These parameters were plotted on the growth and WHO standard deviation charts for both males and females. Overweight and obesity were defined by BMI > 85th and 95th percentile respectively. Laboratory investigations were done in the form of iron profile, liver enzymes, total and direct bilirubin levels, serum urea &creatinine and detection of hepatitis C virus antibodies by ELISA.RESULTS: The weight and BMI were significantly higher in the survivors than controls (P value =0.002 and 0.039 respectively). ALT, total & direct bilirubin, serum ferritin and transferrin saturation were significantly higher in the survivors than the controls (P value = 0.03, 0.036, 0.044, 0.006 and 0.03 respectively). Ten (28.6%) of survivors had hepatitis C antibodies with none (0%) of controls (P value =0.02)CONCLUSIONS: Pediatric ALL survivors are at increased risk of overweight/obesity, hepatic dysfunction in the form of elevated liver enzymes, bilirubin levels and C viral hepatitis. Screening of those survivors for such complications should be considered.Key words: ALL- Survivors – Obesity- Liver.

scholarly journals Sparse estimation for case–control studies with multiple disease subtypes

Biostatistics ◽  
2020 ◽  
Author(s):  
Nadim Ballout ◽  
Cedric Garcia ◽  
Vivian Viallon
Keyword(s):  
Logistic Regression ◽  
Regression Model ◽  
Logistic Regression Model ◽  
Multinomial Logistic Regression ◽  
Conditional Logistic Regression ◽  
Case Control ◽  
Case Control Studies ◽  
Conditional Logistic Regression Model ◽  
Symmetric Formulation ◽  
Disease Subtypes

Summary The analysis of case–control studies with several disease subtypes is increasingly common, e.g. in cancer epidemiology. For matched designs, a natural strategy is based on a stratified conditional logistic regression model. Then, to account for the potential homogeneity among disease subtypes, we adapt the ideas of data shared lasso, which has been recently proposed for the estimation of stratified regression models. For unmatched designs, we compare two standard methods based on $L_1$-norm penalized multinomial logistic regression. We describe formal connections between these two approaches, from which practical guidance can be derived. We show that one of these approaches, which is based on a symmetric formulation of the multinomial logistic regression model, actually reduces to a data shared lasso version of the other. Consequently, the relative performance of the two approaches critically depends on the level of homogeneity that exists among disease subtypes: more precisely, when homogeneity is moderate to high, the non-symmetric formulation with controls as the reference is not recommended. Empirical results obtained from synthetic data are presented, which confirm the benefit of properly accounting for potential homogeneity under both matched and unmatched designs, in terms of estimation and prediction accuracy, variable selection and identification of heterogeneities. We also present preliminary results from the analysis of a case–control study nested within the EPIC (European Prospective Investigation into Cancer and nutrition) cohort, where the objective is to identify metabolites associated with the occurrence of subtypes of breast cancer.

scholarly journals Two Postestimation Commands for Assessing Confounding Effects in Epidemiological Studies

2007 ◽  
Vol 7 (2) ◽  
pp. 183-196 ◽  
Author(s):  
Zhiqiang Wang
Keyword(s):  
Logistic Regression ◽  
Bayesian Information Criterion ◽  
Proportional Hazards ◽  
Conditional Logistic Regression ◽  
Information Criterion ◽  
Epidemiological Studies ◽  
Cox Proportional Hazards ◽  
P Value ◽  
Effect Estimate ◽  
Cox Proportional Hazards Models

Confounding is a major issue in observational epidemiological studies. This paper describes two postestimation commands for assessing confounding effects. One command (confall) displays and plots all possible effect estimates against one of p-value, Akaike information criterion, or Bayesian information criterion. This computing-intensive procedure allows researchers to inspect the variability of the effect estimates from various possible models. Another command (chest) uses a stepwise approach to identify variables that have substantially changed the effect estimate. Both commands can be used after most common estimation commands in epidemiological studies, such as logistic regression, conditional logistic regression, Poisson regression, linear regression, and Cox proportional hazards models.

Abstract 114: Effect of Sodium Bicarbonate on Advanced Cardiac Life Support

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jungyoup Lee
Keyword(s):  
Logistic Regression ◽  
Sodium Bicarbonate ◽  
Life Support ◽  
Conditional Logistic Regression ◽  
Advanced Cardiac Life Support ◽  
Spontaneous Circulation ◽  
Rank Test ◽  
P Value ◽  
Multivariable Logistic Regression Model ◽  
Routine Administration

Introduction: Current guidelines do not support routine administration of sodium bicarbonate during cardiopulmonary resuscitation (CPR). Previous studies did not recommend bicarbonate unless there is severe metabolic acidosis or hyperkalemia. We hypothesized that the sodium bicarbonate, regardless of its effect on long-term outcomes, may improve the chance of achieving return-of-spontaneous circulation (ROSC). Methods: We used out of cardiac arrest registry in our hospital and analyzed retrospectively. The primary endpoint was to assess the association between 1) the timing first administration as well as 2) the total amount of sodium bicarbonate administered until ROSC and the chance of achieving ROSC. The secondary endpoint was to assess whether there is significant decrease in early survival if sodium bicarbonate was administered during CPR. We built multivariable logistic regression model by the use of the amount of sodium bicarbonate, age, initial base deficit, serum potassium level and usual Utstein template factors with their p-value < 0.1 in univariable analysis. Results: Total 697 patients were enrolled. The amount of sodium bicarbonate administered until ROSC (or CPR termination if there is no ROSC) was significantly associated with the chance of ROSC (Odds ratio [OR], 1.10; 95% confidence interval [CI], 1.01-1.19; p=0.028). The association was still valid after additional adjustment with factors with their p-value < 0.1 in univariable conditional logistic regression analysis. (OR, 1.14; 95% CI, 1.01-1.29; p=0.031) The time to first administration of sodium bicarbonate did not show significant univariable association (OR, 0.99; 95% CI, 0.99-1.00; p=0.193). Kaplan-Meyer survival curves showed significantly increased death rate in patients administered with sodium bicarbonate (log-rank test, p=0.002) Conclusion: Administration of higher dose of sodium bicarbonate during CPR was associated with increased chance of achieving ROSC. However, such benefit was negated soon after by higher early mortality rate in the group where sodium bicarbonate was administered.

Risk Factors for Inpatient Acute Venous Thromboembolism (VTE) Despite Thromboprophylaxis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2248-2248
Author(s):  
Tzu-Fei Wang ◽  
Catherine A Wong ◽  
Paul Milligan ◽  
Mark S Thoelke ◽  
Keith F Woeltje ◽  
...  
Keyword(s):  
Risk Factors ◽  
Logistic Regression ◽  
Venous Thromboembolism ◽  
Conflicts Of Interest ◽  
Conditional Logistic Regression ◽  
Hospital Setting ◽  
Care Facility ◽  
Conditional Logistic Regression Model ◽  
Term Care ◽  
Pooled Data

Abstract Abstract 2248 Background: Venous thromboembolism (VTE) is the most common preventable cause of morbidity and mortality in the hospital. Adequate thromboprophylaxis has reduced the rate of hospital-acquired VTE by 50–70%; however, some inpatients still develop VTE despite thromboprophylaxis. Predictors associated with thromboprophylaxis failure are undefined. Objectives: We aimed to identify risk factors for VTE despite use of inpatient thromboprophylaxis. Patients/Methods: We used a case-control study to determine independent predictors of inpatient VTE. We matched 94 cases discharged from the BJC HealthCare system from January 1st, 2010 to May 31st, 2011who developed in-hospital VTE despite thromboprophylaxis (including either pharmacological or mechanical prophylaxis or both) to 272 controls without VTE. Matching was done by hospital, age, and date of discharge. Two thirds of the sample was used as derivation model, while one third was used for validation. We used multivariate conditional logistic regression on the derivation sample to develop a VTE prediction model and validated the model. We repeated conditional logistic regression on the pooled data. Results: Age and sex were well-matched. Mean age was 62.8 years-old in the VTE group and 63.2 years-old in the no-VTE group. Forty-three percent were female in the VTE group, while 49% were female in the no-VTE group. Using conditional logistic regression model in the pooled data, we identified five independent risk factors for in-hospital VTE: hospitalization for cranial surgery (Odds ratio [OR] 16.1, 95% confidence interval [CI] 3.2–80.4, p<0.001), hospitalization in a critical care unit (OR 3.0, 95% CI 1.5–5.9, p=0.002), admission leukocyte count > 13 × 103/mm3(OR 2.7, 95% CI 1.4–5.1, p=0.003), presence of an indwelling central venous catheter (OR 2.5, 95% CI 1.3–4.7, p=0.007), and admission from a long-term care facility (OR 2.1, 95% CI 1.0–4.2, p=0.04). Conclusions: In the hospital setting, we derived and validated five risk factors associated with the development of VTE despite thromboprophylaxis. Clinicians should be vigilant for VTE in these patients and ensure that they have aggressive VTE prophylaxis. Disclosures: No relevant conflicts of interest to declare.

Pediatric Hospital Volume and Induction Mortality in Pediatric Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2653-2653
Author(s):  
Jennifer J. Wilkes ◽  
Sean Hennessy ◽  
Rui Xiao ◽  
Susan R. Rheingold ◽  
Alix E. Seif ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Lymphoblastic Leukemia ◽  
High Volume ◽  
Mortality Rates ◽  
P Value ◽  
Hospital Inpatient ◽  
Exact Test ◽  
Patients Âgés ◽  
Pediatric All ◽  
Volume Outcome

Abstract Introduction: Survival in pediatric acute lymphoblastic leukemia (ALL) has increased dramatically over the past 40 years from less than 10% to 85%. Despite these gains, induction mortality rates have been shown to vary between institutions. This variation may relate to hospital factors such as patient volume. A volume-outcome association describes the relationship between how frequently a service is provided by a hospital to the quality of care received at the patient level. In adult care, higher procedural and patient volume has been associated with improved outcomes. Few studies have investigated a volume-outcome relationship in pediatric leukemia. We hypothesized that an inverse relationship exists between a hospital’s pediatric volume and their pediatric ALL induction mortality rates. Methods: A retrospective cohort of new onset ALL patients ages 0 to <19 years was assembled using three years of consecutive data from the Pediatric Health Information System (PHIS) and Perspective Data Warehouse (Premier). PHIS is comprised of free-standing children’s hospitals while Premier represents community institutions caring for both adult and pediatric patients. The primary outcome was inpatient mortality in the first 60 days after initiation of induction chemotherapy. Hospital pediatric volume was defined as the average annual number of inpatient discharges for patients ages of 1–19-years. Hospitals were then grouped into tertiles as low, medium or high volume. Descriptive analysis represented by counts and percentages with 95% confidence intervals. Fisher’s exact test and the non-parametric tests for trend were applied to assess association between a hospital’s ALL mortality rate and their pediatric volume tertile using STATA version 13. Results: 3456 patients with new onset ALL from 75 individual hospitals were included in our analysis. The induction mortality rate for the entire cohort was 0.87% (30/3456) with a range from 0.58% to 1.2% (Table 1). There was no significant inverse linear trend in mortality across the three pediatric volume categories (p= 0.218). Inpatient induction mortality was lowest in the low pediatric volume institutions, with resultant significant increased induction mortality rate when comparing medium volume institutions and high volume institutions to low volume institutions (Table 1). There was no difference in mortality rates between medium and high volume centers (p=0.468). Conclusions: Induction mortality in this pediatric ALL cohort is low and consistent with previously published literature. Contrary to our hypothesis, we observed a lower induction mortality rate in lowest volume institutions. While this finding may be real, it is likely that there are unmeasured confounders impacting the volume-outcome association in this ALL cohort. For instance, low pediatric volume centers may transfer sicker or more complex patients to medium or high volume centers due to lack of familiarity or comfort caring for a complicated patient with a rare diagnosis. The current dataset is limited and would require merger of alternate data sources to capture patient transfers from low to medium and high volume hospitals. Future analyses of these data will focus on adjusting for severity of illness at presentation among patients at the medium and high volume hospitals to see if an inverse association exists between volume and mortality. Table 1: Hospital Inpatient Volume and Disposition at Last Hospitalization in Induction Hospital Inpatient Pediatric Volume Total ALL patients Percent Mortality [95% CI of frequency] p value** Low (<6000) n= 27 512 0% [0-0.72%]* ref Medium (6000-9000) n=25 1371 1.2% [0.67-1.8%] 0.014 High (>9000) n=23 1573 0.89% [0.48-1.5%] 0.032 Total 75 Hospitals 3456 0.87% [0.58-1.2%] *97.5% one sided confidence interval **p value of Fisher’s exact test with reference as low pediatric volume tertile. Disclosures Rheingold: Novartis: Consultancy.

The Heterogeneous Fusion Gene Landscape in Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4081-4081
Author(s):  
Yanara Marincevic-Zuniga ◽  
Johan Dahlberg ◽  
Sara Nilsson ◽  
Amanda Raine ◽  
Jonas Abrahamsson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
Gene Fusion ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Fusion Genes ◽  
Fusion Transcripts ◽  
Pediatric All

Abstract Background: Next generation sequencing allows for the detection of expressed fusion transcripts across the transcriptome and has spurred the discovery of many novel chimeric transcripts in various cancers. Structural chromosomal rearrangements that lead to fusion transcripts are a hallmark of acute lymphoblastic leukemia (ALL) and serve as markers for diagnosis and stratification of pediatric ALL patients into prognostically relevant subgroups. Improved delineation of structural alterations in ALL could provide additional information for prognosis in ALL and for improved stratification of patients into treatment groups. Methods: To identify novel fusion transcripts in primary pediatric ALL cells we performed whole transcriptome sequencing of 134 BCP and T-ALL patient samples collected at diagnosis. Our study include samples from patients with the well-known ALL subtypes t(12;21)ETV6-RUNX1, high hyperdiploid (51-67 chromosomes), t(9;22)BCR-ABL1, 11q23/MLL and dic(9;20), in addition to patients with undefined karyotype or non-recurrent cytogenetic aberrations ("undefined" and "other") (n=58). FusionCatcher was used for the detection of somatic fusion genes, followed by a stringent filtering pipeline including gene fusion validation by Sanger sequencing in order to reduce the number of false positives. Principal component analysis (PCA) of patients with fusion genes was performed using genome wide gene expression levels and DNA methylation levels (Infinium HumanMethylation450 bead array). Results: We identified and validated 60 unique fusion events in almost half of the analyzed patients (n=69). Of the identified fusion genes, 60% have not previously been reported in ALL or other forms of cancer. The majority of the fusion genes were found in a single patient, but 23% were recurrent, including known ALL fusion genes (n=10) and novel fusion genes (n=7). We found that BCP-ALL samples displayed a higher number of validated fusion genes (54%) compared to the T-ALL samples (28%) moreover in BCP-ALL patients with "other" and "undefined" karyotypes, we detected fusion genes in 71% and 61% of the samples, respectively. High hyperdiploid patients had the lowest rate of validated fusion genes (24%) compared to the other well-known subtypes, where we detected subtype-associated fusion genes in 97% of cases. We also identified promiscuous fusion gene partners, such as ETV6, RUNX1, PAX5 and ZNF384 that fused with up to five different genes. Interestingly, PCA revealed molecularly distinct gene expression and DNA methylation signatures associated with these fusion partners. Conclusion: RNA-sequencing of pediatric ALL cells revealed a detailed view of the heterogeneous fusion gene landscape, identifying both known and novel fusion genes. By grouping samples based on recurrent gene fusion partners we are able to find shared gene expression and DNA methylation patterns compared to other subtypes of ALL, suggesting a shared molecular etiology within these distinct subgroups, offering novel insights into the delineation of fusion genes in ALL. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document