scholarly journals Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics

Blood ◽  
2019 ◽  
Vol 133 (7) ◽  
pp. 724-729 ◽  
Author(s):  
Maoxiang Qian ◽  
Heng Xu ◽  
Virginia Perez-Andreu ◽  
Kathryn G. Roberts ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Causal Variant ◽  
Risk Alleles ◽  
Genome Wide ◽  
A Genome ◽  
Dna Elements ◽  
Regulatory Dna

Abstract Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Characterized by high levels of Native American ancestry, Hispanics are disproportionally affected by this cancer with high incidence and inferior survival. However, the genetic basis for this disparity remains poorly understood because of a paucity of genome-wide investigation of ALL in Hispanics. Performing a genome-wide association study (GWAS) in 940 Hispanic children with ALL and 681 ancestry-matched non-ALL controls, we identified a novel susceptibility locus in the ERG gene (rs2836365; P = 3.76 × 10−8; odds ratio [OR] = 1.56), with independent validation (P = .01; OR = 1.43). Imputation analyses pointed to a single causal variant driving the association signal at this locus overlapping with putative regulatory DNA elements. The effect size of the ERG risk variant rose with increasing Native American genetic ancestry. The ERG risk genotype was underrepresented in ALL with the ETV6-RUNX1 fusion (P < .0005) but enriched in the TCF3-PBX1 subtype (P < .05). Interestingly, ALL cases with germline ERG risk alleles were significantly less likely to have somatic ERG deletion (P < .05). Our results provide novel insights into genetic predisposition to ALL and its contribution to racial disparity in this cancer.

scholarly journals Genome-Wide Association Study of Susceptibility Loci for T-Cell Acute Lymphoblastic Leukemia in Children

2019 ◽  
Vol 111 (12) ◽  
pp. 1350-1357 ◽  
Author(s):  
Maoxiang Qian ◽  
Xujie Zhao ◽  
Meenakshi Devidas ◽  
Wenjian Yang ◽  
Yoshihiro Gocho ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Luciferase Assay ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
A Genome

Abstract Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. Methods We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided. Results A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias. Conclusions These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).

scholarly journals Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia

2016 ◽  
Vol 34 (18) ◽  
pp. 2133-2140 ◽  
Author(s):  
Chengcheng Liu ◽  
Wenjian Yang ◽  
Meenakshi Devidas ◽  
Cheng Cheng ◽  
Deqing Pei ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Pancreatitis ◽  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
Genetic Risk ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Common Variants ◽  
Genome Wide

Purpose Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified. Methods To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors. Results Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10−9). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation. Conclusion Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.

scholarly journals Inherited NUDT15 Variant Is a Genetic Determinant of Mercaptopurine Intolerance in Children With Acute Lymphoblastic Leukemia

2015 ◽  
Vol 33 (11) ◽  
pp. 1235-1242 ◽  
Author(s):  
Jun J. Yang ◽  
Wendy Landier ◽  
Wenjian Yang ◽  
Chengcheng Liu ◽  
Lindsey Hageman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Race And Ethnicity ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Dose Intensity ◽  
Average Dose ◽  
Childhood All ◽  
Curative Therapy ◽  
Genome Wide ◽  
A Genome

Purpose Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL. Patients and Methods The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model. Results MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10−9) and rs116855232 in NUDT15 (P = 8.8 × 10−9), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others. Conclusion We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

scholarly journals A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults

Blood ◽  
2015 ◽  
Vol 125 (4) ◽  
pp. 680-686 ◽  
Author(s):  
Virginia Perez-Andreu ◽  
Kathryn G. Roberts ◽  
Heng Xu ◽  
Colton Smith ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Age Group ◽  
Genome Wide ◽  
A Genome ◽  
Key Points ◽  
Similarities And Differences

Key Points In this first ALL GWAS in AYAs, we determined that inherited GATA3 variants strongly influence ALL susceptibility in this age group. These findings revealed similarities and differences in the genetic basis of ALL susceptibility between young children and AYAs.

scholarly journals Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children

2020 ◽  
Author(s):  
Shawn H R Lee ◽  
Maoxiang Qian ◽  
Wentao Yang ◽  
Jonathan D Diedrich ◽  
Elizabeth Raetz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Molecular Subtype ◽  
Lymphoblastic Leukemia ◽  
Specific Effect ◽  
Genome Wide Association ◽  
Inherited Susceptibility ◽  
Genome Wide ◽  
A Genome

Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 × 10–8 for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 × 10–8 for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis.

scholarly journals Genetic Determinants of Blood Cell Traits Influence Susceptibility to Childhood Acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Linda Kachuri ◽  
Soyoung Jeon ◽  
Andrew T. DeWan ◽  
Catherine Metayer ◽  
Xiaomei Ma ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Blood Cell ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Cell Types ◽  
Genetic Determinants ◽  
Childhood All ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

ABSTRACTAcute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite overlap between genetic risk loci for ALL and hematologic traits, the etiological relevance of dysregulated blood cell homeostasis remains unclear. We investigated this question in a genome-wide association study (GWAS) of ALL (2666 cases, 60,272 controls) and multi-trait GWAS of 9 blood cell indices in the UK Biobank. We identified 3000 blood cell trait-associated (P<5.0×10−8) variants, explaining 4.0% to 23.9% of trait variation, and including 115 loci associated with blood cell ratios (LMR: lymphocyte/monocyte, NLR: neutrophil/lymphocyte, PLR: platelet/lymphocyte). ALL susceptibility was genetically correlated with lymphocyte counts (rg=0.088, p=4.0×10−4) and PLR (rg= −0.072, p=0.0017). In Mendelian randomization analyses, genetically predicted increase in lymphocyte counts was associated with increased ALL risk (Odds ratio (OR)=1.16, p=0.031) and strengthened after accounting for other cell types (OR=1.48, p=8.8×10−4). We observed positive associations with increasing LMR (OR=1.22, p=0.0017) and inverse effects for NLR (OR=0.67, p=3.1×10−4) and PLR (OR=0.80, p=0.002). Our study shows that a genetically induced shift towards higher lymphocyte counts, overall and in relation to monocytes, neutrophils, and platelets, confers an increased susceptibility to childhood ALL.

Genomic Variants Associated with Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-11-SCI-11
Author(s):  
Mary V. Relling
Keyword(s):  
Genetic Variation ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Drug Clearance ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Pharmacokinetic Data ◽  
Clinical Effects ◽  
Childhood All ◽  
Genome Wide ◽  
A Genome

Abstract Abstract SCI-11 Genome-wide interrogations have a role in addressing both the etiology and the responsiveness of childhood acute lymphoblastic leukemia (ALL). Recent work by our own1 and other groups identified common polymorphisms in ARID5B, and to a lesser extent in IKZF1, as predisposing to the development of childhood ALL. Polymorphisms in these two genes can account for ∼ 40% of the population attributable risk of ALL, and differences in the frequency of the minor allele among different ancestral groups can account for a large portion of the differences in the incidence of ALL among different race groups. The association of these inherited polymorphisms with specific ALL subtypes (e.g. ARID5B with risk of hyperdiploid ALL) indicates that germline polymorphisms affect not only risk of ALL but may also affect or confound association analyses between germline variants and the probability of cure of ALL. The biological basis for the prognostic differences that exist among ALL subtypes remain largely unknown, and it is plausible that inherited polymorphisms may affect both susceptibility to subtypes of ALL as well as to drug responsiveness. Genome-wide analyses have also identified polymorphisms associated with eradication of MRD across multiple treatment protocols.2 Polymorphisms in IL15 indicate variants that likely affect the inherent pharmacodynamic responsiveness of ALL to drug-induced apoptosis. Approximately 20% of the polymorphisms associated with MRD were also associated with rapid drug clearance in the host, even though pharmacokinetic data were only available for 2 of the 4–8 medications used during induction. These findings lead us to suggest that perhaps half of the polymorphisms associated with eradication of ALL are related to effects on host drug clearance, and about half have penetrant effects on the inherent responsiveness of the ALL cells themselves. A genome-wide analysis for the determinants of clearance of one such drug, methotrexate, identified a strong effect of polymorphisms in the SLCO1B1 transporter.3 Genome-wide approaches have identified the importance of genes that decades of candidate gene approaches did not reveal, illustrating the utility of an agnostic approach to genotype-phenotype association studies in childhood ALL. 1. Treviño LR, Yang W, French D, et al. Germline genomic variations associated with childhood acute lymphoblastic leukemia. Nat Genet 41:1001–5, 2009. 2. Yang J, Cheng C, Yang W, et al. Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 301:393–403, 2009. 3. Treviño LR, Shimasaki N, Yang W, et al. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol 27:5972–8, 2009. Disclosures: Relling: St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding.

A Genome-Wide Analysis of Variants Influencing Methotrexate Clearance Replicates SLCO1B1.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2466-2466 ◽  
Author(s):  
Laura B. Ramsey ◽  
John C Panetta ◽  
Colton Smith ◽  
Wenjian Yang ◽  
Yiping Fan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
High Dose ◽  
Genome Wide Analysis ◽  
Anion Transporter ◽  
Genome Wide ◽  
A Genome

Abstract Abstract 2466 High-dose methotrexate (HDMTX) is an important element of chemotherapy for acute lymphoblastic leukemia (ALL) and other malignancies. Methotrexate clearance influences cure and toxicity in children with acute lymphoblastic leukemia (ALL). HDMTX schedules and doses vary widely among treatment protocols. The Children's Oncology Group (COG) tested the efficacy of 6 courses of 2 g/m2 over 4 hours versus 1 g/m2 over 24 hours (P9904 and P9905 protocols). Patients were assigned to one of four arms for consolidation: A, 24-hour methotrexate infusion (1 g/m2) and no delayed intensification (DI); B, 4-hour methotrexate infusion (2 g/m2) with no DI; C, 24-hour methotrexate infusion with DI; D, 4-hour methotrexate infusion with DI. We estimated methotrexate clearance for 1279 patients treated on these protocols, with two plasma MTX concentrations per course, using a Bayesian pharmacokinetic modeling approach. Germline genetic variation was assessed using the Affymetrix 6.0 array, and other single nucleotide polymorphisms (SNPs) were imputed based on 1000 Genomes reference data, yielding 5.2 million SNP genotypes evaluable per patient. Average MTX clearance was highly variable, with a median (range) of 164 (65–355) and 109 (49–290) ml/min/m2 for the 24-hour and 4-hour infusions, respectively. Methotrexate clearance was lower in older children (p = 7 × 10−7), girls (p = 2.7 × 10−4), and patients who received a delayed intensification phase during consolidation (p = 0.0022). Adjusting for age, gender, race, and treatment arm, a genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in SLCO1B1(p = 2.1 × 10−11), a gene that encodes for an organic anion transporter that is known to transport methotrexate. This replicates our previous findings (Trevino et al, J Clin Oncol. 2009;27(35):5972-8) that polymorphisms in SLCO1B1 influence methotrexate clearance in ALL patients treated on St. Jude protocols with three different HDMTX schedules. In a combined meta-analysis including the 1279 COG patients and 699 St. Jude patients, and adjusting for age, gender, race, and treatment arm, the association of methotrexate clearance with SLCO1B1 SNP rs4149056 yields a p-value of 3.1 × 10−19 (Figure). Even after adjustment for the rs4149056 SNP, other polymorphisms in SLCO1B1 remained significantly related to methotrexate clearance, indicating that there are multiple variants in SLCO1B1 that can influence methotrexate clearance. Validation of the association of this gene with five different treatment regimens of methotrexate solidifies the robustness of this pharmacogenomic determinant of methotrexate clearance. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document