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.
•Integrating cytogenetic and genomic data in pediatric ALL reveals 2 subgroups with different outcomes independent of other risk factors.•A total of 75% of children on UKALL2003 had a good-risk genetic profile, which predicted an EFS and OS of 94% and 97% at 5 years.
Summary 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).
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.
Key Points
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 × 10−19), 10q21.2 (ARID5B, rs7089424, OR = 1.65, P = 6.69 × 10−19) and 14q11.2 (CEBPE, rs2239633, OR = 1.34, P = 2.88 × 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.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Childhood cancer in high resource settings Kinsey, Sally E.; Picton, Susan V.
Cancer epidemiology,
April 2021, 2021-Apr, 2021-04-00, 20210401, Letnik:
71, Številka:
Pt B
Journal Article
Recenzirano
•Description of pathways to diagnosis and management of childhood cancers in HIC.•Comparison pathways to diagnosis and treatment between HIC and MIC/LIC.•Lack of availability of effective diagnostics ...and therapy leaves a large gap in the overall survival of highly treatable cancers in MIC/LIC.•Experience in HIC demonstrates effective use of local resources and a multidisciplinary team enables a holistic approach in the management of childhood cancer patients.
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.
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.
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 ×10−22), 1.80 (P = 5.90 × 10−28), and 1.27 (P = 4.90 × 10−6), respectively. Furthermore, the risk of ALL increases with an increasing numbers of variant alleles for the 3 loci (ORper-allele = 1.53, 95% confidence interval, 1.44-1.62; Ptrend = 3.49 × 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.
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 × 10−11), irrespective of cell lineage.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
‘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.
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.
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