scholarly journals “SOCIOECONOMIC FACTORS AFFECTING SURVIVAL IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA FROM NORTH-EAST INDIA”

2020 ◽  
pp. 1-3
Author(s):  
Partha Sarathi Roy ◽  
Munlima Hazarika ◽  
Rakesh Kumar Mishra ◽  
BhargabJyoti Saikia ◽  
Gaurav Kumar
Keyword(s):  
Overall Survival ◽  
Developing Countries ◽  
Acute Lymphoblastic Leukemia ◽  
Socioeconomic Factors ◽  
Lymphoblastic Leukemia ◽  
Childhood All ◽  
Female Ratio ◽  
Risk Of Death ◽  
Lower Socioeconomic ◽  
Pediatric All

Acute lymphoblastic leukemia (ALL) is a highly curable childhood cancer with a survival rate of nearly 80% in developed countries but is around 45% in developing countries. This retrospective study analyzed the association between demographic and socioeconomic factors with survival in pediatric ALL. All confirmed cases of pediatric ALL (age <18 years) registered at Dr. B Borooah Cancer Institute between 2010 to 2017 were analyzed using data collected from hospital-based cancer registry and case records. Seventy-five confirmed cases of pediatrics ALL were eligible for the study. The median age of presentation was six years with a male: female ratio 1.9:1. Overall survival at 4-years was 43.8%, with a median survival of 25 months. A trend for higher 4-year overall survival was seen in female children (54.1% versus 37.9%, p=0.097). Patients from rural areas (44% versus 39.5%, p=0.308), with higher maternal education (83.3% versus 41.1%, p=0.161) and patients who did not abandon treatment (49.1% versus 31.2%, p=0.497) had better survival, but the differences were not significant. Four years overall survival in upper-middle, lower-middle, upper-lower, and lower class were 85.7%, 74.9%, 38.1%, and 7.7% respectively (upper-middleversus lower socioeconomic class, p=0.0001).Multivariate analyses confirmed a statistically significant relationship between socioeconomic status and survival, with the upper-middle group had a 90% decreased risk of death compared to the lower socioeconomic group. There is an urgent need for a proper definition of the problems of childhood ALL to introduce appropriate policies for improving survival in developing countries.

scholarly journals Homozygous Deletion of the p16/MTS1 Gene in Pediatric Acute Lymphoblastic Leukemia Is Associated With Unfavorable Clinical Outcome

Blood ◽  
1997 ◽  
Vol 89 (11) ◽  
pp. 4161-4166 ◽  
Author(s):  
Ursula R. Kees ◽  
Paul R. Burton ◽  
Changlong Lü ◽  
David L. Baker
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Clinical Outcome ◽  
Lymphoblastic Leukemia ◽  
Homozygous Deletion ◽  
Cell Phenotype ◽  
P16 Gene ◽  
Childhood All ◽  
Risk Of Death ◽  
Increased Risk

Abstract The p16 gene (MTS1, CDKN2, p16INK4A, CDKI) encoding an inhibitor of cyclin-dependent kinase 4 (cdk4) has been found to be deleted in various types of tumors, including leukemia, and is thought to code for a tumor suppressor gene. Our preliminary findings on eight pediatric patients with acute lymphoblastic leukemia (ALL) suggested that the survival of patients carrying a homozygous p16 gene deletion was significantly inferior to that of those without a deletion. The present study on 48 patients tested the hypothesis that the clinical outcome for pediatric ALL patients is correlated with the presence or absence of the p16 gene. Overall, nine of 48 children (18.3%) carried a homozygous p16 deletion. Such deletions were significantly more common (P = .003) among T-ALL patients (five of eight, 62.5%) than among precursor-B-ALL patients (four of 40, 10.0%). Of nine patients exhibiting p16 deletions, eight (88.9%) were classified as high-risk patients by the recognized prognostic factors of age, white blood cell count, and T-cell phenotype. The 4-year event-free survival in the study population as a whole was 72.7%. Without adjustment for other risk factors (univariate model), the presence of a homozygous p16 deletion was associated with a markedly increased probability of both relapse (P = .0003) and death (P = .002). These findings raise the question of whether the p16 deletion itself confers an increased risk of relapse after adjusting for the known risk factors. In this analysis, the estimated risk multiplier factor for relapse in patients carrying the p16 deletion was 14.0 (P = .0004) and for the risk of death 15.6 (P = .0008). We therefore conclude that the presence of a homozygous p16 deletion may well be an important risk factor for both relapse and death in childhood ALL, and that its prognostic effect is not a consequence of confounding by other factors already known to influence outcome in this disease.

scholarly journals Incidence and Clinical Relevance of TEL/AML1 Fusion Genes in Children With Acute Lymphoblastic Leukemia Enrolled in the German and Italian Multicenter Therapy Trials

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 571-577 ◽  
Author(s):  
Arndt Borkhardt ◽  
Giovanni Cazzaniga ◽  
Susanne Viehmann ◽  
Maria Grazia Valsecchi ◽  
Wolf Dieter Ludwig ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Dna Index ◽  
Childhood All ◽  
Pediatric All ◽  
Aml1 Gene ◽  
B Lineage ◽  
The Impact

The molecular approach for the analysis of leukemia associated chromosomal translocations has led to the identification of prognostic relevant subgroups. In pediatric acute lymphoblastic leukemia (ALL), the most common translocations, t(9; 22) and t(4; 11), have been associated with a poorer clinical outcome. Recently the TEL gene at chromosome 12p13 and the AML1 gene at chromosome 21q22 were found to be involved in the translocation t(12; 21)(p13; q22). By conventional cytogenetics, however, this chromosomal abnormality is barely detectable and occurs in less than 0.05% of childhood ALL. To investigate the frequency of the molecular equivalent of the t(12; 21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankfurt-Münster (BFM) and Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) multicenter ALL therapy trials. We have analyzed 334 unselected cases of pediatric ALL patients consecutively referred over a period of 5 and 9 months, respectively. The overall incidence of the t(12; 21) in pediatric ALL is 18.9%. The 63 cases positive for the TEL/AML1 chimeric products ranged in age between 1 and 12 years, and all but one showed CD10 and pre-B immunophenotype. Interestingly, one case displayed a pre-pre–B immunophenotype. Among the B-lineage subgroup, the t(12; 21) occurs in 22.0% of the cases. Fifteen of 61 (24.6%) cases coexpressed at least two myeloid antigens (CD13, CD33, or CDw65) in more than 20% of the gated blast cells. DNA index was available for 59 of the 63 TEL/AML1 positive cases; a hyperdiploid DNA content (≥1.16) was detected in only four patients, being nonhyperdiploid in the remaining 55. Based on this prospective analysis, we retrospectively evaluated the impact of TEL/AML1 in prognosis by identifying the subset of B-lineage ALL children enrolled in the closed German ALL-BFM-90 and Italian ALL-AIEOP-91 protocols who had sufficient material for analysis. A total of 342 children were investigated for the presence of TEL/AML1 fusion gene and 99 cases (28.9%) were positive. The patients expressing the TEL/AML1 fusion mRNA appeared to have a better event-free survival (EFS) than the patients who lacked this chimeric product. Whereas three of the TEL/AML1 positive cases (3.0%) have relapsed to date, 27 patients without TEL/AML1 rearrangement (11.1%) suffered from relapse. To date, the only subset of B-lineage ALL with a favorable prognosis has been the hyperdiploid group (DNA index ≥1.16 <1.6). Our findings reinforce the need to include the molecular screening of the t(12; 21) translocation within ongoing prospective ALL trials to prove definitively its prognostic impact.

scholarly journals Identification of a Seven-lncRNA-mRNA Signature for Recurrence and Prognostic Prediction in Relapsed Acute Lymphoblastic Leukemia Based on WGCNA and LASSO Analyses

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Haiyan Qi ◽  
Long Chi ◽  
Xiaogang Wang ◽  
Xing Jin ◽  
Wensong Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Characteristic Curve ◽  
High Risk Group ◽  
Curve Analysis ◽  
Clinical Relapse ◽  
Messenger Rnas ◽  
Childhood All

Abnormal expressions of long noncoding RNAs (lncRNAs) and protein-encoding messenger RNAs (mRNAs) are important for the development of childhood acute lymphoblastic leukemia (ALL). This study developed an lncRNA-mRNA integrated classifier for the prediction of recurrence and prognosis in relapsed childhood ALL by using several transcriptome data. Weighted gene coexpression network analysis revealed that green, turquoise, yellow, and brown modules were preserved across the TARGET, GSE60926, GSE28460, and GSE17703 datasets, and they were associated with clinical relapse and death status. A total of 184 genes in these four modules were differentially expressed between recurrence and nonrecurrence samples. Least absolute shrinkage and selection operator analysis showed that seven genes constructed a prognostic signature (including one lncRNA: LINC00652 and six mRNAs: INSL3, NIPAL2, REN, RIMS2, RPRM, and SNAP91). Kaplan-Meier curve analysis observed that patients in the high-risk group had a significantly shorter overall survival than those of the low-risk group. Receiver operating characteristic curve analysis demonstrated that this signature had high accuracy in predicting the 5-year overall survival and recurrence outcomes, respectively. LINC00652 may function by coexpressing with the above prognostic genes (INSL3, SNAP91, and REN) and lipid metabolism-related genes (MIA2, APOA1). Accordingly, this lncRNA-mRNA-based classifier may be clinically useful to predict the recurrence and prognosis for childhood ALL. These genes represent new targets to explain the mechanisms for ALL.

scholarly journals Association between the TPMT*3C (rs1142345) Polymorphism and the Risk of Death in the Treatment of Acute Lymphoblastic Leukemia in Children from the Brazilian Amazon Region

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1132
Author(s):  
Darlen Cardoso de Carvalho ◽  
Luciana Pereira Colares Leitão ◽  
Fernando Augusto Rodrigues Mello Junior ◽  
Alayde Vieira Wanderley ◽  
Tatiane Piedade de Souza ◽  
...  
Keyword(s):  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Brazilian Amazon ◽  
Childhood All ◽  
Risk Of Death ◽  
Native American Ancestry ◽  
High Contribution ◽  
Tpmt Gene

Acute lymphoblastic leukemia (ALL) is the leading cause of death from pediatric cancer worldwide. However, marked ethnic disparities are found in the treatment of childhood ALL with less effective results and higher mortality rates being obtained in populations with a high level of Native American ancestry. Genetic variations of the patient can affect resistance to ALL chemotherapy and potentially play an important role in this disparity. In the present study, we investigated the association of 16 genetic polymorphisms with the cell and metabolic pathways of the chemotherapeutic agents used in the treatment of ALL with the risk of death in treating childhood ALL in patients with a high contribution of Amerindian ancestry, coming from the Brazilian Amazon. The study included 121 patients with B-cell ALL treated with the BFM-2002 protocol. We are the first to identify the association between the TPMT gene rs1142345 polymorphism and the high risk of death in treating childhood ALL. Patients with the CC genotype had an approximately 25.5 times higher risk of dying during treatment of the disease than patients with other genotypes (p = 0.019). These results may help elucidate how the patient’s genetic characteristics contribute to the mortality disparity in populations with a high contribution of Native American ancestry. The rs1142345 variant of the TPMT gene could be used as a potential marker to early stratify patients at high risk of death in treating childhood ALL in the investigated population.

scholarly journals Residence in a Hispanic Enclave Is Associated with Inferior Overall Survival among Children with Acute Lymphoblastic Leukemia

2021 ◽  
Vol 18 (17) ◽  
pp. 9273
Author(s):  
Jeremy M. Schraw ◽  
Erin C. Peckham-Gregory ◽  
Amy E. Hughes ◽  
Michael E. Scheurer ◽  
Sandi L. Pruitt ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Cox Regression ◽  
Lymphoblastic Leukemia ◽  
Hispanic Children ◽  
White Children ◽  
Risk Of Death ◽  
Increased Risk ◽  
The Social ◽  
High Concentrations

Hispanic children with acute lymphoblastic leukemia (ALL) experience poorer overall survival (OS) than non-Hispanic White children; however, few studies have investigated the social determinants of this disparity. In Texas, many Hispanic individuals reside in ethnic enclaves—areas with high concentrations of immigrants, ethnic-specific businesses, and language isolation, which are often socioeconomically deprived. We determined whether enclave residence was associated with ALL survival, overall and among Hispanic children. We computed Hispanic enclave index scores for Texas census tracts, and classified children (N = 4083) as residing in enclaves if their residential tracts scored in the highest statewide quintile. We used Cox regression to evaluate the association between enclave residence and OS. Five-year OS was 78.6% for children in enclaves, and 77.8% for Hispanic children in enclaves, both significantly lower (p < 0.05) than the 85.8% observed among children not in enclaves. Children in enclaves had increased risk of death (hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.01–1.49) after adjustment for sex, age at diagnosis, year of diagnosis, metropolitan residence and neighborhood socioeconomic deprivation and after further adjustment for child race/ethnicity (HR 1.19, 95% CI 0.97–1.45). We observed increased risk of death when analyses were restricted to Hispanic children specifically (HR 1.30, 95% CI 1.03–1.65). Observations suggest that children with ALL residing in Hispanic enclaves experience inferior OS.

scholarly journals Genomic Analyses of Pediatric Acute Lymphoblastic Leukemia Ph+ and Ph-Like—Recent Progress in Treatment

2021 ◽  
Vol 22 (12) ◽  
pp. 6411
Author(s):  
Agnieszka Kaczmarska ◽  
Patrycja Śliwa ◽  
Joanna Zawitkowska ◽  
Monika Lejman
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Targeted Therapies ◽  
Lymphoblastic Leukemia ◽  
Childhood All ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Genomic Analyses ◽  
Pediatric All

Pediatric acute lymphoblastic leukemia (ALL) with t(9;22)(q34;q11.2) is a very rare malignancy in children. Approximately 3–5% of pediatric ALL patients present with the Philadelphia chromosome. Previously, children with Ph+ had a poor prognosis, and were considered for allogeneic stem cell transplantation (allo-HSCT) in their first remission (CR1). Over the last few years, the treatment of childhood ALL has significantly improved due to standardized research protocols. Hematopoietic stem cell transplantation (HSCT) has been the gold standard therapy in ALL Ph+ patients, but recently first-generation tyrosine kinase inhibitor (TKI)-imatinib became a major milestone in increasing overall survival. Genomic analyses give the opportunity for the investigation of new fusions or mutations, which can be used to establish effective targeted therapies. Alterations of the IKZF1 gene are present in a large proportion of pediatric and adult ALL Ph+ cases. IKZF1 deletions are present in ~15% of patients without BCR-ABL1 rearrangements. In BCR-ABL1-negative cases, IKZF1 deletions have been shown to have an independent prognostic impact, carrying a three-fold increased risk of treatment failure. The prognostic significance of IKZF1 gene aberrations in pediatric ALL Ph+ is still under investigation. More research should focus on targeted therapies and immunotherapy, which is not associated with serious toxicity in the same way as classic chemotherapy, and on the improvement of patient outcomes. In this review, we provide a molecular analysis of childhood ALL with t(9;22)(q34;q11.2), including the Ph-like subtype, and of treatment strategies.

Incidence and Clinical Relevance of TEL/AML1 Fusion Genes in Children With Acute Lymphoblastic Leukemia Enrolled in the German and Italian Multicenter Therapy Trials

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 571-577 ◽  
Author(s):  
Arndt Borkhardt ◽  
Giovanni Cazzaniga ◽  
Susanne Viehmann ◽  
Maria Grazia Valsecchi ◽  
Wolf Dieter Ludwig ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Dna Index ◽  
Childhood All ◽  
Pediatric All ◽  
Aml1 Gene ◽  
B Lineage ◽  
The Impact

Abstract The molecular approach for the analysis of leukemia associated chromosomal translocations has led to the identification of prognostic relevant subgroups. In pediatric acute lymphoblastic leukemia (ALL), the most common translocations, t(9; 22) and t(4; 11), have been associated with a poorer clinical outcome. Recently the TEL gene at chromosome 12p13 and the AML1 gene at chromosome 21q22 were found to be involved in the translocation t(12; 21)(p13; q22). By conventional cytogenetics, however, this chromosomal abnormality is barely detectable and occurs in less than 0.05% of childhood ALL. To investigate the frequency of the molecular equivalent of the t(12; 21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankfurt-Münster (BFM) and Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) multicenter ALL therapy trials. We have analyzed 334 unselected cases of pediatric ALL patients consecutively referred over a period of 5 and 9 months, respectively. The overall incidence of the t(12; 21) in pediatric ALL is 18.9%. The 63 cases positive for the TEL/AML1 chimeric products ranged in age between 1 and 12 years, and all but one showed CD10 and pre-B immunophenotype. Interestingly, one case displayed a pre-pre–B immunophenotype. Among the B-lineage subgroup, the t(12; 21) occurs in 22.0% of the cases. Fifteen of 61 (24.6%) cases coexpressed at least two myeloid antigens (CD13, CD33, or CDw65) in more than 20% of the gated blast cells. DNA index was available for 59 of the 63 TEL/AML1 positive cases; a hyperdiploid DNA content (≥1.16) was detected in only four patients, being nonhyperdiploid in the remaining 55. Based on this prospective analysis, we retrospectively evaluated the impact of TEL/AML1 in prognosis by identifying the subset of B-lineage ALL children enrolled in the closed German ALL-BFM-90 and Italian ALL-AIEOP-91 protocols who had sufficient material for analysis. A total of 342 children were investigated for the presence of TEL/AML1 fusion gene and 99 cases (28.9%) were positive. The patients expressing the TEL/AML1 fusion mRNA appeared to have a better event-free survival (EFS) than the patients who lacked this chimeric product. Whereas three of the TEL/AML1 positive cases (3.0%) have relapsed to date, 27 patients without TEL/AML1 rearrangement (11.1%) suffered from relapse. To date, the only subset of B-lineage ALL with a favorable prognosis has been the hyperdiploid group (DNA index ≥1.16 &lt;1.6). Our findings reinforce the need to include the molecular screening of the t(12; 21) translocation within ongoing prospective ALL trials to prove definitively its prognostic impact.

scholarly journals Long-Term Effects of Pediatric Acute Lymphoblastic Leukemia Chemotherapy: Can Recent Findings Inform Old Strategies?

2021 ◽  
Vol 11 ◽  
Author(s):  
Zeina N. Al-Mahayri ◽  
Mohammad M. AlAhmad ◽  
Bassam R. Ali
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cardiac Toxicity ◽  
Lymphoblastic Leukemia ◽  
Genomic Medicine ◽  
Malignant Neoplasms ◽  
Childhood All ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Acute Neuropathy ◽  
Pediatric All

During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors’ late adverse events, including secondary malignant neoplasms (SMNs), cardiac toxicity, neurotoxicity, bone toxicity, hepatic dysfunction, visual changes, obesity, impact on fertility, and neurocognitive effects have been evaluated. Throughout this review, we attempted to answer a fundamental question: can the recent molecular findings mitigate pediatric-ALL chemotherapy’s long-term sequelae on adult survivors? For SMNs, few genetic predisposition factors have been identified including TP53 and POT1 variants. Other treatment-related risk factors have been identified such as anthracyclines’ possible association with breast cancer in female survivors. Cardiotoxicity is another significant and common adverse event with some germline variants been found, albeit with conflicting evidence, to increase the risk of cardiac toxicity. For peripheral neurotoxicity, vincristine is the primary neurotoxic agent in ALL regimens. Some germline genetic variants were found to be associated with the vincristine neurotoxic effect’s vulnerability. However, these were mainly detected with acute neuropathy. Moreover, the high steroid doses and prolonged use increase bone toxicity and obesity risk with some pharmacogenetic biomarkers were associated with increased steroid sensitivity. Therefore, the role of these biomarkers in tailoring steroid choice and dose is a promising research area. Future directions in pediatric ALL treatment should consider the various opportunities provided by genomic medicine. Understanding the molecular bases underlying toxicities will classify patients into risk groups and implement a closer follow-up to those at higher risk. Pharmacogenetic-guided dosing and selecting between alternative agents have proven their efficacy in the short-term management of childhood ALL. It is the right time to think about a similar approach for the life-long consequences on survivors.

Evidence for a Single Step Mechanism in the Origin of Hyperdiploid Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1966-1966 ◽  
Author(s):  
Kajsa Paulsson ◽  
Helena Morse ◽  
Thoas Fioretos ◽  
Mikael Behrendtz ◽  
Bodil Strombeck ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Single Step ◽  
Chromosome 21 ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
General Mechanism ◽  
Childhood All ◽  
Abnormal Mitosis ◽  
Allele Dosage ◽  
Pediatric All

Abstract High hyperdiploidy (>50 chromosomes) in childhood acute lymphoblastic leukemia (ALL) is characterized by non-random multiple trisomies and tetrasomies, involving in particular chromosomes X, 4, 6, 8, 10, 14, 17, 18, and 21. It is the most common cytogenetic subgroup in pediatric ALL, but in spite of this, the mechanisms behind its formation remain elusive. Four different pathways are possible: (1) initial near-haploidy followed by doubling of the chromosomes, (2) prior polyploidization with subsequent losses of chromosomes, (3) sequential gains of chromosomes in consecutive cell divisions, and (4) a simultaneous gain of all additional chromosomes in a single abnormal mitosis. Although these alternatives are difficult to distinguish experimentally, investigations of possible uniparental disomies (UPDs) and of the allelic ratios of loci located on tetrasomic chromosomes may provide some clues. In a previous study of 10 cases of hyperdiploid childhood ALL, we could exclude the first pathway as a general mechanism. Furthermore, the results did not favor the second alternative. Finally, our findings of equal allele dosage for chromosome 21 loci in cases with tetrasomy 21 suggested that the hyperdiploidy arose by a simultaneous gain of chromosomes. However, because all disomies and tetrasomies were not investigated, formation via a polyploid state or by a sequential gain could not be definitely excluded. In the present study, we have addressed this issue further by investigating 15 new cases of hyperdiploid childhood ALL using a total of 57 polymorphic microsatellite markers mapped to 23 of the 24 human chromosomes. Ten of the cases were analyzed with multicolor fluorescence in situ hybridization (M-FISH) and the remaining five with interphase FISH using probes for X, 4, 6, 8, 10, 14, 17, 18, and 21. Markers localized to all disomic and all tetrasomic chromosomes were then applied. One case displayed multiple UPDs and a non-typical pattern with only tetrasomies; this ALL probably arose via a near-haploid pathway. Two other cases had UPDs for 4/9 and 2/14 disomic chromosomes, respectively, and may have originated via a polyploid state. However, in the vast majority of the cases (12/15) there was no evidence for any UPDs, excluding that the hyperdiploidy originated by the near-haploid or polyploid mechanisms. Investigating the tetrasomies, 25 of a total of 27 tetrasomies present among the 15 cases displayed equal allele dosages, indicating a simultaneous gain of chromosomes as opposed to sequential gains. The two tetrasomies with unequal allele dosages were present in the same case, suggesting that this ALL constituted an exception. In conclusion, the results of the present study strongly suggest that hyperdiploidy in childhood ALL generally arises by a simultaneous gain of all additional chromosomes in a single abnormal mitosis.

The Incidence and Prognostic Significance of 9p21 Abnormalities In Pediatric Acute Lymphoblastic Leukemia Patients – the IWK Experience

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1705-1705
Author(s):  
Brett Gardiner ◽  
Barbara Morash ◽  
Christie Riddell ◽  
Hao Wang ◽  
Conrad V Fernandez ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Small Sample ◽  
Chromosome 9 ◽  
Prognostic Impact ◽  
Aberrant Methylation ◽  
Childhood All ◽  
Pediatric All

Abstract Abstract 1705 Background: Outcomes in acute lymphoblastic leukemia (ALL), the most common childhood malignancy, have improved significantly due to risk-based multi-agent chemotherapy strategies derived from diagnostic advances in cytogenetics and molecular biology. Characterization of recurrent genetic lesions has enabled further prognostic stratification on recent clinical trials. Abnormalities involving the short arm of chromosome 9 are well-documented in pediatric ALL. Three critical tumor suppressors: CDKN2a (p16INK4a), CDKN2b (p15INK4b) and p14ARF have been localized to band 9p21. While 9p21 abnormalities have been reported in 10% of childhood ALL, their prognostic significance remains uncertain and may depend on which of these genes are lost/inactivated. Moreover, 9p deletions may be cryptic and/or not readily identified by standard G-banding techniques. We investigated the incidence and prognostic significance of 9p21 abnormalities identified retrospectively in pediatric ALL patients. Methods: A total of 76 children were diagnosed with ALL at the IWK Health Centre in Halifax, Nova Scotia from 2000–2005. Cell pellets were available for analysis on 48 patients. Chart review was conducted retrospectively. Approval was obtained by the IWK Research Ethics Board. 9p21 abnormalities were assessed by two modalities: 1) fluorescence in-situ hybridization (FISH) using a commercial p16 probe; and 2) methylation specific multiplex ligation-dependent probe amplification (MS-MLPA), using SALSA MLPA kit ME024-A1 9p21 CDKN2A/2B region (MRC Holland). Results: Of the 48 samples studied by FISH, 18 (38%) had a 9p21 deletion, only 4 of which were previously identified by G-banding. MLPA was performed on 40 samples and identified a total of 18 (45%) patients with a 9p21 deletion, 5 of which were not identified by FISH. Aberrant methylation at CDKN2b (p15INK4b) was found by MLPA in 19 patients (46%). Overall, 32 of 48 (67%) patients were determined to have an abnormal 9p21, representing a substantially greater frequency than previously reported. The detection rate for deletions at 9p21 between FISH and MLPA, was not statistically different (p=0.31). Interestingly, all patients with T-cell disease (n=5) had an abnormal 9p21, suggesting an association between this immunophenotype and 9p21 abnormalities (p=0.02). Overall, 9p21 abnormalities were associated with National Cancer Institute (NCI) high risk criteria (p=0.04), specifically white blood cell count >50,000/μL at diagnosis (p=0.019) and a higher percentage of leukemic blasts in the peripheral blood (p=0.016). Only four B-cell lineage patients in our cohort relapsed, three of which had 9p21 abnormalities and one of these ultimately died of disease. Conclusions: Using FISH and MLPA, our study has revealed a much higher incidence of 9p21 abnormalities in childhood ALL than has previously been described. Moreover, our findings demonstrate an association with high risk features and possibly inferior prognosis. It is possible that the lack of consistent reports linking 9p21 abnormalities to prognosis are related to suboptimal ascertainment. A small sample size in our study prevents the conclusive determination of an independent prognostic impact. However, our results justify the need for a larger multi-center investigation to evaluate how 9p21 abnormalities might affect ALL outcome and possibly influence future risk stratification for determining treatment. Disclosures: No relevant conflicts of interest to declare.

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