GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21

Wiemels, Joseph L.; Walsh, Kyle M.; Smith, Adam J. de; Metayer, Catherine; Gonseth, Semira; Hansen, Helen M.; Francis, Stephen; Ojha, Juhi; Смирнов, Иван; Barcellos, Lisa F.; Xiao, Xiaorong; Morimoto, Libby; McKean‐Cowdin, Roberta; Wang, Rong; Yu, Herbert; Hoh, Josephine; DeWan, Andrew T.; Ma, Xiaomei

doi:10.1038/s41467-017-02596-9

Cited by 79 publications

(95 citation statements)

References 51 publications

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“…1,3–6 A number of genetic variants have also been associated with increased risk of leukemia. 7,8 Furthermore, there is reasonably consistent evidence of a slightly increased risk associated with large birth weight relative to gestational time. 9 A higher risk has also been suggested for older parental age, delivery by Cesarean section, and paternal smoking.…”

Section: Introductionmentioning

confidence: 82%

Radiation exposure from computerized tomography and risk of childhood leukemia: Finnish register-based case-control study of childhood leukemia (FRECCLE)

Nikkilä

Raitanen²,

Lohi

et al. 2018

Haematologica

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The only well-established risk factors for childhood leukemia are high-dose ionizing radiation and Down syndrome. Computerized tomography is a common source of low-dose radiation. In this study, we examined the magnitude of the risk of childhood leukemia after pediatric computed tomography examinations. We evaluated the association of computed tomography scans with risk of childhood leukemia in a nationwide register-based case-control study. Cases (n=1,093) were identified from the population-based Finnish Cancer Registry and three controls, matched by gender and age, were randomly selected for each case from the Population Registry. Information was also obtained on birth weight, maternal smoking, parental socioeconomic status and background gamma radiation. Data on computed tomography scans were collected from the ten largest hospitals in Finland, covering approximately 87% of all pediatric computed tomography scans. Red bone marrow doses were estimated with NCICT dose calculation software. The data were analyzed using exact conditional logistic regression analysis. A total of 15 cases (1.4%) and ten controls (0.3%) had undergone one or more computed tomography scans, excluding a 2-year latency period. For one or more computed tomography scans, we observed an odds ratio of 2.82 (95% confidence interval: 1.05 – 7.56). Cumulative red bone marrow dose from computed tomography scans showed an excess odds ratio of 0.13 (95% confidence interval: 0.02 – 0.26) per mGy. Our results are consistent with the notion that even low doses of ionizing radiation observably increase the risk of childhood leukemia. However, the observed risk estimates are somewhat higher than those in earlier studies, probably due to random error, although unknown predisposing factors cannot be ruled out.

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Section: Introductionmentioning

confidence: 82%

Radiation exposure from computerized tomography and risk of childhood leukemia: Finnish register-based case-control study of childhood leukemia (FRECCLE)

Nikkilä

Raitanen²,

Lohi

et al. 2018

Haematologica

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“…A recent GWAS of blood cell traits identified a genome-wide significant SNP rs3011641 in near-perfect LD with rs11591377 (r 2 =0.94 in Europeans and r 2 =0.99 in Latinos), in which the major allele was associated with a higher percentage of myeloid cells that are granulocytes 51 , and which in our study was associated with ALL risk at P meta = 2.4 × 10 −10 . Mirroring this finding, the novel 8q24 locus identified in our recent GWAS of ALL displays chromosomal contact with a region overlapping several GWAS SNPs associated with blood cell traits, including granulocyte percentage of myeloid cells 9, 51 .…”

Section: Discussionmentioning

confidence: 84%

“…Sample acquisition for the California-based Childhood Cancer Record Linkage Project (CCRLP) GWAS of ALL is described in detail in Wiemels et al . 9 . In brief, newborn dried bloodspots (DBS) for cases and controls were obtained from the California Biobank Program, California Department of Public Health (CDPH), Genetic Disease Screening Program.…”

Section: Methodsmentioning

confidence: 99%

“…In a recent California-based GWAS of childhood ALL (using the same study population as current analyses), we identified novel SNP associations at chromosome 17q12-q21.1, which harbors the hematopoietic transcription factor IKZF3 , and at chromosome 8q24, within a gene desert that appears to interact with the MYC oncogene via long-range chromatin interactions 9 . We also replicated previously reported loci, including genome-wide significant associations at the chromosome 10p12 region containing PIP4K2A and BMI1 .…”

Section: Introductionmentioning

confidence: 94%

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BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia

Smith

Walsh

Francis

et al. 2018

Intl Journal of Cancer

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Genome-wide association studies of childhood acute lymphoblastic leukemia (ALL) have identified regions of association at PIP4K2A and upstream of BMI1 at chromosome 10p12.31-12.2. The contribution of both loci to ALL risk and underlying functional variants remain to be elucidated. We carried out single nucleotide polymorphism (SNP) imputation across chromosome 10p12.31-12.2 in Latino and non-Latino white ALL cases and controls from two independent California childhood leukemia studies, and additional Genetic Epidemiology Research on Aging study controls. Ethnicity-stratified association analyses were performed using logistic regression, with meta-analysis including 3,133 cases (1,949 Latino, 1,184 non-Latino white) and 12,135 controls (8,584 Latino, 3,551 non-Latino white). SNP associations were identified at both BMI1 and PIP4K2A. After adjusting for the lead PIP4K2A SNP, genome-wide significant associations remained at BMI1, and vice-versa (p < 10 ), supporting independent effects. Lead SNPs differed by ethnicity at both peaks. We sought functional variants in tight linkage disequilibrium with both the lead Latino SNP among Admixed Americans and lead non-Latino white SNP among Europeans. This pinpointed rs11591377 (p = 2.1 x 10 ) upstream of BMI1, residing within a hematopoietic stem cell enhancer of BMI1, and which showed significant preferential binding of the risk allele to MYBL2 (p = 1.73 x 10 ) and p300 (p = 1.55 x 10 ) transcription factors using binomial tests on ChIP-Seq data from a SNP heterozygote. At PIP4K2A, we identified rs4748812 (p = 1.3 x 10 ), which alters a RUNX1 binding motif and demonstrated chromosomal looping to the PIP4K2A promoter. Fine-mapping chromosome 10p12 in a multi-ethnic ALL GWAS confirmed independent associations and identified putative functional variants upstream of BMI1 and at PIP4K2A.

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“…Heterogeneity within the survivor cohorts (eg, by first primary type, age at exposure) and outcome definitions (eg, by combining all subsequent malignancies together) may further hamper generalizability of the findings. Importantly, the risks associated with variants in each of the GWAS described earlier were generally higher than those in most GWAS of first primary sporadic cancers, with per-allele risk estimates typically ~2-fold or greater for subsequent malignancies compared with 1.1 to 1.2 for most sporadic cancers, except for certain types, such as testicular cancer and acute lymphoblastic leukemia/lymphoma [67, 68]. It remains to be seen if these higher effect sizes will persist as the findings are replicated in additional independent populations, or whether they represent a so-called winner’s curse, whereby the effect sizes are overestimated in the initial discovery studies.…”

Section: Germline Genetic Variation and Risk Of Radiation Therapy–relmentioning

confidence: 99%

Radiogenomic Predictors of Adverse Effects following Charged Particle Therapy

Morton

Ricks-Santi

West

et al. 2018

International Journal of Particle Therapy

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Radiogenomics is the study of genomic factors that are associated with response to radiation therapy. In recent years, progress has been made toward identifying genetic risk factors linked with late radiation-induced adverse effects. These advances have been underpinned by the establishment of an international Radiogenomics Consortium with collaborative studies that expand cohort sizes to increase statistical power and efforts to improve methodologic approaches for radiogenomic research. Published studies have predominantly reported the results of research involving patients treated with photons using external beam radiation therapy. These studies demonstrate our ability to pool international cohorts to identify common single nucleotide polymorphisms associated with risk for developing normal tissue toxicities. Progress has also been achieved toward the discovery of genetic variants associated with radiation therapy–related subsequent malignancies. With the increasing use of charged particle therapy (CPT), there is a need to establish cohorts for patients treated with these advanced technology forms of radiation therapy and to create biorepositories with linked clinical data. While some genetic variants are likely to impact toxicity and second malignancy risks for both photons and charged particles, it is plausible that others may be specific to the radiation modality due to differences in their biological effects, including the complexity of DNA damage produced. In recognition that the formation of patient cohorts treated with CPT for radiogenomic studies is a high priority, efforts are underway to establish collaborations involving institutions treating cancer patients with protons and/or carbon ions as well as consortia, including the Proton Collaborative Group, the Particle Therapy Cooperative Group, and the Pediatric Proton Consortium Registry. These important radiogenomic CPT initiatives need to be expanded internationally to build on experience gained from the Radiogenomics Consortium and epidemiologists investigating normal tissue toxicities and second cancer risk.

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GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21

Cited by 79 publications

References 51 publications

Radiation exposure from computerized tomography and risk of childhood leukemia: Finnish register-based case-control study of childhood leukemia (FRECCLE)

Radiation exposure from computerized tomography and risk of childhood leukemia: Finnish register-based case-control study of childhood leukemia (FRECCLE)

BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia

Radiogenomic Predictors of Adverse Effects following Charged Particle Therapy

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