ABSTRACT
Treatment of childhood cancer in High income countries (HIC) has been a success story of the 20th century with data demonstrating ever increasing survival. Some countries (for example, the UK) have national and regional registries providing high quality data, whilst in other countries the lack of population based data makes comparison impossible. In middle and low income countries (MIC and LIC) the incidence of childhood cancer appears to be lower than in HIC, almost certainly due to the lack of diagnosing and reporting of cases. There may be poor understanding and recognition of symptoms, presentation to traditional healers, poor access to healthcare facilities in rural areas and lack of diagnostic testing. Once on treatment, abandonment of further care can be multifactorial in underlying cause but subsequent relapse and death may add to suspicion of "western" medicine. Additionally, the presenting symptoms of childhood cancer can mimic common infectious diseases such as malaria so that cases remain undiagnosed. By reflecting on some common examples of childhood cancer it can be helpful to identify the points on the pathway to diagnosis and treatment which demonstrate the differences between HIC and MIC/LIC. Some interventions, such as funding for travel to treatment centres, accommodation and treatment, can make the difference between some treatment and no treatment. Highlighting these opportunities for change will improve outcomes in childhood cancer and raise standards of care for paediatrics in general. We have described the pathway to diagnosis and management of childhood cancers in HIC and presented the pathways for common malignancies in HIC and comparators for MIC/LIC to encourage supportive dialogue to improve measures to widen global access to diagnosis and management for children with these conditions. A longer term goal would be to support registries for population-based data collection as part of wider understanding of cancer on a global scale.
Subject(s)
Developed Countries/statistics & numerical data , Neoplasms/diagnosis , Neoplasms/therapy , Child , Developing Countries/statistics & numerical data , Humans , Incidence , Neoplasms/epidemiology , Registries , Survival AnalysisABSTRACT
The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
ABSTRACT
'Cure models' offer additional information to traditional epidemiological approaches to assess survival for cancer patients by simultaneously estimating the proportion cured and the survival of those 'uncured'. The proportion cured is a summary of long-term survival while the median survival time of the uncured provides important information on those who are not long-term survivors. Population-based trends in the cure proportion and survival of the uncured for childhood acute lymphoblastic leukaemia (ALL) by clinical prognostic risk factors were estimated using flexible parametric cure models, based on overall survival and event-free survival. Children aged 1-17 years diagnosed between 1990 and 2011 in Yorkshire, UK, were included (n = 492). The percentage cured increased from 77% (95% confidence interval 70-84%) in 1990-1997 to 89% (84-93%) in 2003-2011, while the median survival time of the uncured decreased from 3·2 years (2·2-4·1 years) to 0·7 years (0-1·5 years). Models based on event-free survival showed a similar trend. The 5-year cumulative incidence of relapse substantially decreased from 35% in 1990-97 to 9% in 2003-2011. These results show selective improvement in survival between 1990 and 2011 with a significant reduction in the risk of relapse alongside a reduced absolute duration of survival for those destined to be uncured.
Subject(s)
Models, Theoretical , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Survivors , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Mortality/trends , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Recurrence , Risk Factors , Survival Analysis , Treatment Outcome , United KingdomABSTRACT
Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.
Subject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Core Binding Factor Alpha 2 Subunit/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Glycosyltransferases/genetics , HLA Antigens/genetics , Humans , Male , Oncogene Proteins, Fusion/genetics , Polymorphism, Single Nucleotide , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Prognosis , Risk FactorsABSTRACT
BACKGROUND: Principal Treatment Centres (PTC) were established to provide age-appropriate care as well as clinical expertise for children and young people with cancer. However, little is known about the effects of specialist treatment centres on survival outcomes especially for teenagers and young adults. This population-based study aimed to describe access to PTC and the associated trends in survival for 0-24 year olds accounting for stage of disease at presentation and treatment. METHODS: Patients diagnosed from 1998-2009 aged 0-24 years were extracted from the Yorkshire Specialist Register of Cancer in Children and Young People, including information on all treating hospitals, followed-up until 31st December 2014. The six commonest cancer types were included: leukaemia (n = 684), lymphoma (n = 558), CNS tumours (n = 547), germ cell tumours (n = 364), soft tissue sarcomas (n = 171) and bone tumours (n = 163). Treatment was categorised into three groups: 'all', 'some' or 'no' treatment received at a PTC. Treatment at PTC was examined by diagnostic group and patient characteristics. Overall survival was modelled using Cox regression adjusting for case-mix including stage, treatment and other socio-demographic and clinical characteristics. RESULTS: Overall 72% of patients received all their treatment at PTC whilst 13% had no treatment at PTC. This differed by diagnostic group and age at diagnosis. Leukaemia patients who received no treatment at PTC had an increased risk of death which was partially explained by differences in patient case-mix (adjusted Hazard Ratio (HR) = 1.73 (95%CI 0.98-3.04)). Soft tissue sarcoma patients who had some or no treatment at PTC had better survival outcomes, which remained after adjustment for patient case-mix (adjusted HR = 0.48 (95%CI 0.23-0.99)). There were no significant differences in outcomes for other diagnostic groups (lymphoma, CNS tumours, bone tumours and germ cell tumours). For leukaemia patients survival outcomes for low risk patients receiving no treatment at PTC were similar to high risk patients who received all treatment at PTC, implying a benefit for care at the PTC. CONCLUSION: This study demonstrates that for leukaemia patients receiving treatment at a PTC is associated with improved survival that may compensate for a poorer prognosis presentation. However, further information on risk factors is needed for all diagnostic groups in order to fully account for differences in patient case-mix.
Subject(s)
Neoplasms/mortality , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Registries , Survival Rate , United Kingdom , Young AdultABSTRACT
Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio = 2.42, P = 3.45 × 10(-19)). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the CDKN2A transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm.
Subject(s)
Chromosomes, Human, Pair 9/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Genetic Predisposition to Disease/epidemiology , Genetic Predisposition to Disease/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Exons/genetics , Genetic Variation/genetics , Genome-Wide Association Study , Humans , Male , Polymorphism, Single Nucleotide/genetics , Prevalence , Risk Factors , United Kingdom/epidemiologyABSTRACT
Although children with acute lymphoblastic leukemia (ALL) generally have a good outcome, some patients do relapse and survival following relapse is poor. Altered DNA methylation is highly prevalent in ALL and raises the possibility that DNA methylation-based biomarkers could predict patient outcome. In this study, genome-wide methylation analysis, using the Illumina Infinium HumanMethylation450 BeadChip platform, was carried out on 52 diagnostic patient samples from 4 genetic subtypes [ETV6-RUNX1, high hyperdiploidy (HeH), TCF3-PBX1 and dic(9;20)(p11-13;q11)] in a 1:1 case-control design with patients who went on to relapse (as cases) and patients achieving long-term remission (as controls). Pyrosequencing assays for selected loci were used to confirm the array-generated data. Non-negative matrix factorization consensus clustering readily clustered samples according to genetic subgroups and gene enrichment pathway analysis suggested that this is in part driven by epigenetic disruption of subtype specific signaling pathways. Multiple bioinformatics approaches (including bump hunting and individual locus analysis) were used to identify CpG sites or regions associated with outcome. However, no associations with relapse were identified. Our data revealed that ETV6-RUNX1 and dic(9;20) subtypes were mostly associated with hypermethylation; conversely, TCF3-PBX1 and HeH were associated with hypomethylation. We observed significant enrichment of the neuroactive ligand-receptor interaction pathway in TCF3-PBX1 as well as an enrichment of genes involved in immunity and infection pathways in ETV6-RUNX1 subtype. Taken together, our results suggest that altered DNA methylation may have differential impacts in distinct ALL genetic subtypes.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Core Binding Factor Alpha 2 Subunit/genetics , DNA Methylation/genetics , DNA-Binding Proteins/genetics , Epigenomics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins c-ets/genetics , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Child , Child, Preschool , CpG Islands/genetics , Genome, Human , Humans , Infant , Oncogene Proteins, Fusion/genetics , Pre-B-Cell Leukemia Transcription Factor 1 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/classification , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Recurrence , ETS Translocation Variant 6 ProteinABSTRACT
Gender-specific differences in survival by clinical trial era in Yorkshire were assessed for children with acute lymphoid leukaemia (ALL) enrolled onto UKALLXI, ALL97/99 or UKALL2003 (n = 630; 1990-2011). For males, there was a non-significant improvement in survival for ALL97/99 [hazard ratio (HR) = 0·77; 95% confidence interval (CI) 0·43-1·42) and a significant improvement for UKALL2003 (HR = 0·50; 95%CI 0·25-0·99) compared to UKALLXI. For females, survival was significantly improved for ALL97/99 (HR = 0·33; 95%CI 0·14-0·78), and non-significantly improved for UKALL2003 (HR = 0·51; 95%CI 0·25-1·08) compared to UKALLXI. Modest overall survival improvements masked clinically important gender-specific changes over time by trial era, requiring confirmation in larger population-based studies.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Sex Characteristics , Adolescent , Child , Child, Preschool , Clinical Trials as Topic , Disease-Free Survival , Female , Humans , Infant , Male , Retrospective Studies , Survival Rate , United Kingdom/epidemiologyABSTRACT
BACKGROUND: Little aetiological epidemiological research has been undertaken for major cancers occurring in teenagers and young adults (TYA). Population mixing, as a possible proxy for infectious exposure, has been well researched for childhood malignancies. We aimed to investigate effects of population mixing in this older age group using an English national cancer dataset. METHODS: Cases of leukaemia, lymphoma and central nervous system (CNS) tumours amongst 15-24 year olds in England (diagnosed 1996-2005) were included in the study. Data were obtained by ward of diagnosis and linked to 1991 census variables including population mixing (Shannon index); data on person-weighted population density and deprivation (Townsend score) were also used and considered as explanatory variables. Associations between TYA cancer incidence and census variables were investigated using negative binomial regression, and results presented as incidence rate ratios (IRR) with 95% confidence intervals (CI). RESULTS: A total of 6251 cases of leukaemia (21%), lymphoma (49%) and CNS tumours (30%) were analysed. Higher levels of population mixing were associated with a significant decrease in the incidence of CNS tumours (IRR=0.83, 95% CI=0.75-0.91), accounted for by astrocytomas and 'other CNS tumours'; however, there was no association with leukaemia or lymphoma. Incidence of CNS tumours and lymphoma was 3% lower in more deprived areas (IRR=0.97, 95% CI=0.96-0.99 and IRR=0.97, 95% CI=.96-0.98 respectively). Population density was not associated with the incidence of leukaemia, lymphoma or CNS tumours. CONCLUSIONS: Our results suggest a possible role for environmental risk factors with population correlates in the aetiology of CNS tumours amongst TYAs. Unlike studies of childhood cancer, associations between population mixing and the incidence of leukaemia and lymphoma were not observed.
Subject(s)
Central Nervous System Neoplasms/epidemiology , Central Nervous System Neoplasms/etiology , Leukemia/epidemiology , Leukemia/etiology , Lymphoma/epidemiology , Lymphoma/etiology , Adolescent , Adult , Central Nervous System Neoplasms/history , Child , Databases, Factual , England/epidemiology , Female , History, 20th Century , History, 21st Century , Humans , Incidence , Leukemia/history , Lymphoma/history , Male , Young AdultABSTRACT
Recent genomic studies have provided a refined genetic map of acute lymphoblastic leukemia (ALL) and increased the number of potential prognostic markers. Therefore, we integrated copy-number alteration data from the 8 most commonly deleted genes, subordinately, with established chromosomal abnormalities to derive a 2-tier genetic classification. The classification was developed using 809 ALL97/99 patients and validated using 742 United Kingdom (UK)ALL2003 patients. Good-risk (GR) genetic features included ETV6-RUNX1, high hyperdiploidy, normal copy-number status for all 8 genes, isolated deletions affecting ETV6/PAX5/BTG1, and ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. All other genetic features were classified as poor risk (PR). Three-quarters of UKALL2003 patients had a GR genetic profile and a significantly improved event-free survival (EFS) (94%) compared with patients with a PR genetic profile (79%). This difference was driven by a lower relapse rate (4% vs 17%), was seen across all patient subgroups, and was independent of other risk factors. Even genetic GR patients with minimal residual disease (>0.01%) at day 29 had an EFS in excess of 90%. In conclusion, the integration of genomic and cytogenetic data defines 2 subgroups with distinct responses to treatment and identifies a large subset of children suitable for treatment deintensification.
Subject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Child , Child, Preschool , Cohort Studies , Core Binding Factor Alpha 2 Subunit/genetics , Cytogenetic Analysis , Female , Gene Deletion , Gene Dosage , Genes, p16 , Genomics , Humans , Infant , Kaplan-Meier Estimate , Male , Neoplasm Proteins/genetics , Oncogene Proteins, Fusion/genetics , PAX5 Transcription Factor/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/classification , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prognosis , Proto-Oncogene Proteins c-ets/genetics , Repressor Proteins/genetics , Risk Factors , ETS Translocation Variant 6 ProteinABSTRACT
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 × 10(-9)) and 10p14 marked by rs3824662 (OR = 1.31; P = 8.62 × 10(-12)). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P < .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development.
Subject(s)
Chromosomes, Human, Pair 10 , GATA3 Transcription Factor/genetics , Phenotype , Phosphotransferases (Alcohol Group Acceptor)/genetics , Polymorphism, Single Nucleotide , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Age Factors , Alleles , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Child , Exons , Female , Genetic Loci , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Introns , Male , Middle Aged , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Survival AnalysisABSTRACT
BACKGROUND: We aimed to examine evidence for an infectious aetiology among teenagers and young adults (TYA) by analysing monthly seasonality of diagnosis and birth amongst 15-24 year olds diagnosed with cancer in England. METHODS: Cases of leukaemia, lymphoma and central nervous system (CNS) tumours were derived from the national TYA cancer register (1996-2005). Incidence rates (IR) and trends were assessed using Poisson regression. Seasonality of diagnosis and birth was assessed using Poisson and logistic regression respectively with cosine functions of varying periods. RESULTS: There were 6251 cases diagnosed with leukaemia (n = 1299), lymphoma (n = 3070) and CNS tumours (n = 1882), the overall IR was 92 (95% CI 89-96) per 1,000,000 15-24 year olds per year.There was significant evidence of seasonality around the time of diagnosis for Hodgkin's lymphoma (P < 0.001) with a peak in February, and for 'other CNS tumours' (P = 0.010) with peaks in December and June. Birth peaks for those with 'other Gliomas' (Gliomas other than Astrocytoma and Ependymoma) were observed in May and November (P = 0.015). CONCLUSION: Our novel findings support an infectious aetiological hypothesis for certain subgroups of TYA cancer in England. Further work will examine correlation with specific infections occurring around the time of birth and diagnosis within certain diagnostic groups.
Subject(s)
Neoplasms/epidemiology , Seasons , Adolescent , England/epidemiology , Female , Humans , Incidence , Male , Young AdultABSTRACT
PURPOSE: It is often assumed that prolonged time to diagnosis (TTD) for cancer negatively influences overall survival and survivorship through advanced stage disease at diagnosis. This systematic review assesses existing early diagnosis research in childhood and young adult cancer and aims to identify whether a consensus exists within the literature in relation to the terminology and methodologies used to investigate TTD in this population. METHODS: Medline, Embase, the Centre for Reviews and Dissemination database and Cochrane library were searched for papers on children and young adults (0-30 years) published from 1948 to the present. RESULTS: Of the 1665 potentially eligible citations identified, 32 papers met the inclusion criteria. The majority of work was in European (n=15) or North American (n=8) populations. Most work focused on brain tumours (n=10), retinoblastomas (n=5) and bone and soft tissue sarcomas (n=4). The majority of studies were in hospital-based settings (n=25), with only seven papers adopting a population-based setting. Summary statistics presented were mostly median TTD, the skewed distribution of the data meant comparisons between studies based on medians were difficult and combining studies within a meta-analysis was not appropriate. CONCLUSIONS: Within the childhood and young adult population, TTD for cancer varies between diagnostic groups and with age at diagnosis in the majority of studies. In order that clear conclusions can be drawn from early diagnosis research in children and young adults, specific criteria identifying circumstances in which delay has occurred should accompany a defined time line to diagnosis or treatment in every study.
Subject(s)
Neoplasms/diagnosis , Adolescent , Age Factors , Child , Early Diagnosis , Humans , Prognosis , Time Factors , Young AdultABSTRACT
A role for specific human leukocyte antigen (HLA) variants in the etiology of childhood acute lymphoblastic leukemia (ALL) has been extensively studied over the last 30 years, but no unambiguous association has been identified. To comprehensively study the relationship between genetic variation within the 4.5 Mb major histocompatibility complex genomic region and precursor B-cell (BCP) ALL risk, we analyzed 1075 observed and 8176 imputed single nucleotide polymorphisms and their related haplotypes in 824 BCP-ALL cases and 4737 controls. Using these genotypes we also imputed both common and rare alleles at class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1, HLA-DQA1, and HLA-DQB1) HLA loci. Overall, we found no statistically significant association between variants and BCP-ALL risk. We conclude that major histocompatibility complex-defined variation in immune-mediated response is unlikely to be a major risk factor for BCP-ALL.
Subject(s)
Haplotypes/genetics , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class I/genetics , Polymorphism, Single Nucleotide/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Alleles , Case-Control Studies , Child , Child, Preschool , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Humans , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathologyABSTRACT
Deregulated expression of CRLF2 (CRLF2-d) arises via its juxtaposition to the IGH@ enhancer or P2RY8 promoter. Among 865 BCP-ALL children treated on MRC ALL97, 52 (6%) had CRLF2-d, but it was more prevalent among Down syndrome patients (54%). P2RY8-CRLF2 (n = 43) was more frequent than IGH@-CRLF2 (n = 9). CRLF2-d was not associated with age, sex, or white cell count, but IGH@-CRLF2 patients were older than P2RY8-CRLF2 patients (median 8 vs 4 years, P = .0017). Patients with CRLF2-d were more likely to present with enlarged livers and spleens (38% vs 18%, P < .001). CRLF2-d was not seen in conjunction with established chromosomal translocations but 6 (12%) cases had high hyperdiploidy, and 5 (10%) had iAMP21. Univariate analysis suggested that CRLF2-d was associated with an inferior outcome: (event-free survival [EFS] hazard ratio 2.27 [95% confidence interval 1.48-3.47], P < .001; OS 3.69 [2.34-5.84], P < .001). However, multivariate analysis indicated that its effect was mediated by other risk factors such as cytogenetics and DS status (EFS 1.45 [0.88-2.39], P = .140; OS 1.90 [1.08-3.36], P = .027). Although the outcome of IGH@-CRLF2 patients appeared inferior compared with P2RY8-CRLF2 patients, the result was not significant (EFS 2.69 [1.15-6.31], P = .023; OS 2.86 [1.15-6.79], P = .021). Therefore, we concluded that patients with CRLF2-d should be classified into the intermediate cytogenetic risk group.
Subject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Receptors, Cytokine/genetics , Adolescent , Child , Child, Preschool , Chromosome Aberrations , Disease-Free Survival , Down Syndrome/complications , Down Syndrome/genetics , Down Syndrome/immunology , Enhancer Elements, Genetic , Female , Gene Expression , Genes, Immunoglobulin Heavy Chain , Humans , In Situ Hybridization, Fluorescence , Infant , Kaplan-Meier Estimate , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Promoter Regions, Genetic , Receptors, Purinergic P2/genetics , Translocation, GeneticABSTRACT
Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 x 10(-11)), irrespective of cell lineage.
Subject(s)
Chromosomes, Human, Pair 9 , Genes, p16 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Case-Control Studies , Genetic Predisposition to Disease , Genome-Wide Association Study , HumansABSTRACT
BACKGROUND: Chromosomal abnormalities in childhood acute lymphoblastic leukaemia are well established disease markers and indicators of outcomes. However, the long-term prognosis and independent prognostic effect of some abnormalities has been questioned. Also, little is known about the association between cytogenetics and the characteristics of relapse (eg, time and site of relapse) that are known to predict outcome after relapse. METHODS: We analysed cytogenetic data from 1725 children with B-cell precursor acute lymphoblastic leukaemia who were included in the UK Medical Research Council ALL97/99 study and followed up for a median time of 8.2 years. Univariate and multivariate analysis were done to examine risk of relapse, event-free survival, and overall survival associated with 21 chromosomal abnormalities and three cytogenetic risk groups constructed from these data. FINDINGS: Two chromosomal abnormalities were associated with a significantly better outcome (ETV6-RUNX1, hazard ratio [HR] 0.51, 95% CI 0.38-0.70 and high hyperdiploidy, 0.60, 0.47-0.78), whereas five abnormalities were associated with an increased risk of relapse (intrachromosomal amplification of chromosome 21 [iAMP21], 6.04, 3.90-9.35; t(9;22), 3.55, 2.21-5.72; MLL translocations, 2.98, 1.71-5.20; abnormal 17p, 2.09, 1.30-3.37; and loss of 13q, 1.87, 1.09-3.20). Multivariate analysis incorporating age, white-cell count, and treatment parameters showed that six cytogenetic abnormalities (ETV6-RUNX1, high hyperdiploidy, iAMP21, t(9;22), loss of 13q, and abnormal 17p) retained their significance for effect on relapse risk. Based on these data, patients were classified into good, intermediate, and poor cytogenetic risk groups. Slow early treatment response correlated with cytogenetic risk group: 34 of 460 (7%) in the good-risk group, 22 of 211 (10%) in the intermediate-risk group, and 27 of 95 (28%) in the poor-risk group had a slow response (p<0.0001). Additionally, the proportion of patients with a very early (<18 months) relapse varied by cytogenetic risk group: eight of 129 (6%) patients in the good-risk group had a very early relapse, compared with 24 of 98 (24%) in the intermediate-risk group, and 37 of 82 (45%) in the poor-risk group (p<0.0001). However, there was no difference in the site of relapse by cytogenetic risk group. INTERPRETATION: Individual chromosomal abnormalities are strong independent indicators of outcome, especially risk of relapse. Diagnostic cytogenetics identifies patients with a higher rate of relapse and those who are likely to have a high-risk relapse. FUNDING: Leukaemia and Lymphoma Research (LLR).
Subject(s)
Chromosome Aberrations , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Child , Child, Preschool , Humans , Infant , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Prognosis , Survival AnalysisABSTRACT
Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we analyzed 824 ALL cases and 2398 controls genotyped for 292 200 tagging SNPs. Across the genome, cumulative distribution of ROH was not significantly different between cases and controls. Four common ROH at 10p11.2-10q11.21, 1p31.1, 19p13.2-3, and 20q11.1-23 were, however, associated with ALL risk at P less than .01 (including 1 ROH to which the erythropoietin receptor [EPOR] gene maps, P = .005) but were nonsignificant after adjusting for multiple testing. Our findings make it unlikely that levels of measured homozygosity, caused by autozygosity, uniparental isodisomy, or hemizygosity, play a major role in defining BCP-ALL risk in predominantly outbred populations.
Subject(s)
Homozygote , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Case-Control Studies , Child , Child, Preschool , Chromosome Mapping , Female , Genes, Recessive , Genome-Wide Association Study , Humans , Infant , Male , Polymorphism, Single Nucleotide , Receptors, Erythropoietin/genetics , Risk Factors , United Kingdom , White People/geneticsABSTRACT
Recent genome-wide association data have implicated genetic variation at 7p12.2 (IKZF1), 10q21.2 (ARIDB5), and 14q11.2 (CEBPE) in the etiology of B-cell childhood acute lymphoblastic leukemia (ALL). To verify and further examine the relationship between these variants and ALL risk, we genotyped 1384 cases of precursor B-cell childhood ALL and 1877 controls from Germany and the United Kingdom. The combined data provided statistically significant support for an association between genotype at each of these loci and ALL risk; odds ratios (OR), 1.69 (P = 7.51 x10(-22)), 1.80 (P = 5.90 x 10(-28)), and 1.27 (P = 4.90 x 10(-6)), respectively. Furthermore, the risk of ALL increases with an increasing numbers of variant alleles for the 3 loci (OR(per-allele) = 1.53, 95% confidence interval, 1.44-1.62; P(trend) = 3.49 x 10(-42)), consistent with a polygenic model of disease susceptibility. These data provide unambiguous evidence for the role of these variants in defining ALL risk underscoring approximately 64% of cases.
Subject(s)
Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 7/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Alleles , CCAAT-Enhancer-Binding Proteins/genetics , Case-Control Studies , Child , DNA-Binding Proteins/genetics , Female , Genetic Predisposition to Disease , Genotype , Germany , Humans , Ikaros Transcription Factor/genetics , Male , Middle Aged , Models, Genetic , Odds Ratio , Polymorphism, Single Nucleotide , Transcription Factors/genetics , United KingdomABSTRACT
To identify risk variants for childhood acute lymphoblastic leukemia (ALL), we conducted a genome-wide association study of two case-control series, analyzing the genotypes with respect to 291,423 tagging SNPs in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601, odds ratio (OR) = 1.69, P = 1.20 x 10(-19)), 10q21.2 (ARID5B, rs7089424, OR = 1.65, P = 6.69 x 10(-19)) and 14q11.2 (CEBPE, rs2239633, OR = 1.34, P = 2.88 x 10(-7)). The 10q21.2 (ARID5B) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide new insight into disease causation of this specific hematological cancer. Notably, all three risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors.