scholarly journals Diet as a Potential Moderator for Genome Stability and Immune Response in Pediatric Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 413
Author(s):  
Shanshan Wang ◽  
Christopher A. Maxwell ◽  
Neha M. Akella
Keyword(s):  
Immune System ◽  
Hormonal Regulation ◽  
Genome Stability ◽  
Lymphoblastic Leukemia ◽  
Childhood Development ◽  
Pediatric Leukemia ◽  
Childhood All ◽  
Immune System Development ◽  
Increased Risk ◽  
Essential Components

Pediatric leukemias are the most prevalent cancers affecting children in developed societies, with childhood acute lymphoblastic leukemia (ALL) being the most common subtype. As diet is a likely modulator of many diseases, this review focuses on the potential for diet to influence the incidence and progression of childhood ALL. In particular, the potential effect of diets on genome stability and immunity during the prenatal and postnatal stages of early childhood development are discussed. Maternal diet plays an integral role in shaping the bodily composition of the newborn, and thus may influence fetal genome stability and immune system development. Indeed, higher birth weights of newborns are associated with increased risk of ALL, which suggests in-utero biology may shape the evolution of preleukemic clones. Postnatally, the ingestion of maternal breastmilk both nourishes the infant, and provides essential components that strengthen and educate the developing immune system. Consistently, breast-feeding associates with decreased risk of ALL development. For children already suffering from ALL, certain dietary regimens have been proposed. These regimens, which have been validated in both animals and humans, alter the internal hormonal environment. Thus, hormonal regulation by diet may shape childhood metabolism and immunity in a manner that is detrimental to the evolution or expansion of preleukemic and leukemic ALL clones.

scholarly journals Nutritional status and physical activity of childhood leukemia survivors

2014 ◽  
Vol 54 (2) ◽  
pp. 67
Author(s):  
Conny Tanjung ◽  
Johannes Bondan Lukito ◽  
Prima Dyarti Meylani
Keyword(s):  
Physical Activity ◽  
Nutritional Status ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Induction Phase ◽  
Childhood All ◽  
Increased Risk ◽  
Long Term Survivors ◽  
First Time

Background Acute lymphoblastic leukemia (ALL), the mostcommon malignancy of childhood, has an overall cure rate ofapproximately 80%. Long-term survivors of childhood ALL areat increased risk for obesity and physical inactivity that may leadto the development of diabetes, dyslipidemia, metabolic syndrome,as well as cardiovascular dis eases, and related mortality in theyears following treatment.Objective To evaluate the physical activity and the propensityfor developing obesity longer term in ALL survivors.Methods This retrospective cohort study included all ALLsurvivors from Pantai Indah Kapuk (PIK) Hospital. We assessedtheir physical activity and nutritional status at the first time ofALL diagnosis an d at the time of interview.Results Subjects were 15 ALL survivors aged 7 to 24 years. Themedian fo llow up time was 6.4 years (range 3 to 10 years). Only2 out of 15 survivors were overweight and n one were obese.All survivors led a sedentary lifestyle. Most female subjectshad increased BMI, though most were not overweight/obese.Steroid therapy in the induction phase did not increase the riskof developing obesity in ALL survivors.Conclusion Lon g-term survivors of childh ood ALL do not meetphysical activity recommendations according to the CDC (Centersfor Disease Control). Howevei; steroid therapy do not seem tolead to overweight/obesity in ALL survivors.

scholarly journals Absence of oncogene amplifications and occasional activation of N-ras in lymphoblastic leukemia of childhood

Blood ◽  
1986 ◽  
Vol 67 (6) ◽  
pp. 1698-1704 ◽  
Author(s):  
S Rodenhuis ◽  
JL Bos ◽  
RM Slater ◽  
H Behrendt ◽  
M van 't Veer ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
Enzyme Analysis ◽  
Ras Gene ◽  
Childhood All ◽  
Increased Risk ◽  
Oligonucleotide Hybridization ◽  
Mutational Activation ◽  
Philadelphia Chromosome Positive

To examine whether determination of (1) the copynumber or restriction pattern of certain oncogenes or (2) the mutational activation of the N- ras gene might contribute to the risk classification of acute lymphoblastic leukemia of childhood (ALL), we investigated DNA isolated from lymphoblasts of untreated patients. Restriction enzyme analysis of cellular oncogenes was performed on DNA of 25 patients. No rearrangements could be demonstrated within or near the genes c-myc, c- myb, c-abl, bcr, c-Ki-ras, and N-ras. No amplifications of these genes nor of N-myc or c-Ha-ras were present. Eight of 21 patients were heterozygote for “rare” Ha-ras allelic restriction fragments that have been associated with an increased risk of developing a malignancy. These patients were clinically indistinguishable from patients lacking these fragments. The breakpoint cluster region (bcr) that is rearranged in all patients with Philadelphia chromosome positive chronic myeloid leukemia, was normal in all cases, including at least one patient with Philadelphia chromosome positive ALL. A 2.8 kb HindIII fragment of a hitherto unknown gene or pseudogene related to v-myb probably derives from the Y chromosome. Nineteen patients were examined for point mutations in the N-ras gene, using a novel synthetic oligonucleotide hybridization assay. In two patients activating point mutations were present, both in positions 1 of the 12th codon. Both patients were somewhat older than the others (16 and 11 years), had L2 morphology, and were shown to have high growth fractions of tumor in their bone marrow.

scholarly journals Study of Some Biochemical Parameters in Iraqi Children with Acute Lymphoblastic Leukemia

2015 ◽  
Vol 12 (2) ◽  
pp. 371-378
Author(s):  
Baghdad Science Journal
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Biochemical Parameters ◽  
Serum Proteins ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
Total Serum ◽  
Childhood All ◽  
Marrow Cavity ◽  
Increased Risk

Leukemia or cancer of the blood is the most common childhood cancer, Acute lymphoblastic leukemia (ALL), is the most common form of leukemia that occurs in children. It is characterized by the presence of too many immature white blood cells in the child’s blood and bone marrow, Acute lymphoblastic leukemia can occur in adults too, treatment is different for children. Children with ALL develop symptoms related to infiltration of blasts in the bone marrow, lymphoid system, and extramedullary sites, such as the central nervous system (CNS). Common constitutional indications consist of fatigue (50%), pallor (25%), fever (60%), and weight loss (26%). Infiltration of blast cells in the marrow cavity and periosteum often lead to bone pain (23%) and disturbance of normal hematopoiesis. Thrombocytopenia with platelet counts less than 100,000 are seen in approximately 75% of patients. About 40% of patients with childhood ALL present with hemoglobin levels less than 7 g/dL. Although leukocyte counts greater than 50,000/mm3 occur in 20% of cases, neutropenia defined as an absolute neutrophil count less than 500 is common at presentation and is associated with an increased risk of infection. The aim of this study was to investigate the differentiations in some biochemical parameters (Hb, PCV, total serum proteins Aspartate amino transferase(AST), Alanin amino transferase (ALT), and Malondialdehyde (MDA) in blood which can be conceder as a marker of ALL. Samples were collected from 50 patients (between 1-16 years old) diagnosed with ALL after one month treatment with induction therapy, compared with 30 control samples taken from healthy persons at the same age . The ALT and MDA showed a significant increase p < 0.001 and p

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.

Perforin Polymorphism A91V and Susceptibility to Childhood Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1453-1453
Author(s):  
Parinda A. Mehta ◽  
Stella M. Davies ◽  
Ashish Kumar ◽  
Meenakshi Devidas ◽  
Susan Lee ◽  
...  
Keyword(s):  
Nk Cells ◽  
Blood Donors ◽  
Lymphoblastic Leukemia ◽  
Active Form ◽  
Low Frequency ◽  
Variant Allele ◽  
P Value ◽  
Childhood All ◽  
Genotype Frequencies ◽  
Increased Risk

Abstract Perforin plays a key role in the cytotoxicity of NK cells and cytotoxic T lymphocytes. Genetic mutations in perforin gene (PRF1) give rise to 30–40% of cases of familial hemophagocytic lymphohistiocytosis. We recently studied two boys who had been treated for PreB ALL and subsequently developed HLH. Both showed decreased perforin expression in NK cells and were found to be heterozygous for PRF1 A91V. The functional consequences of the PRF1 A91V (resulting from C272T transition) are controversial; between 3 and 17% of apparently normal people are heterozygous for this polymorphism depending on the population studied. Recent data suggest that A91V results in conformational change that may impair processing of perforin protein to the active form, and that the polymorphism may increase susceptibility to ALL in children (Trambas et al, Blood2005; 106:932; Santoro et al, Haematologica2005;90:697). We have genotyped 655 normal blood donors and 2,272 children with ALL treated on Pediatric Oncology Group 9900 clinical trials. Genotyping was performed using a specific PCR assay (Taqman). Genotypes in the normal US blood donors showed significant variation in allele frequency by race, with a very low frequency of the variant allele in black controls (0.7% compared with 4% in white controls). Allele frequencies did not vary by gender and genotype frequencies were in Hardy Weinberg equilibrium (whites C/C 92%; C/T 8%; T/T 0.2%). In light of the low frequency of the variant allele in blacks, analysis of leukemia cases was restricted to a comparison of white cases and white controls. Analyses were performed for all B-lineage ALL cases combined, and were also further stratified for known genetic subtypes of ALL. Perforin genotype CC Perforin genotype CT or TT p-value (cases versus controls Controls (n=507) 464 (91.5%) 43 (8.5%) - Cases (all; n= 1321) 1198 (90.7%) 123 (9.3%) 0.58 BCR-ABL 22 (76%) 7 (24%) 0.0048 Trisomy 4,10 238 (93.7%) 16 (6.3%) 0.29 TEL-AML1 250 (90.6%) 26 (9.4%) 0.66 E2A-PBX 24 (92.3%) 2 (7.7%) 0.89 MLL abn. 40 (87%) 6 (13%) 0.29 Hyperdiploid 244 (92.4%) 20 (7.6%) 0.66 Hypodiploid 8 (100%) 0 (0%) 0.40 Taken together, these data indicate that the A91V polymorphism is not associated with an overall increased risk of childhood ALL, in contrast to the previous report. PRF1 A91V was identified with significantly increased frequency in children with BCR-ABL positive ALL. However, this observation includes a relatively small number of cases and the potential association should be explored further, perhaps in adult ALL series in which the frequency of BCR-ABL positivity is likely to be high.

Acute Lymphocytic Leukemia and Down Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-8-SCI-8
Author(s):  
Shai Izraeli
Keyword(s):  
Down Syndrome ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Mtor Inhibitors ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
Childhood All ◽  
Increased Risk ◽  
The Common

Abstract SCI-8 Children with Down syndrome are at a markedly increased risk for acute lymphoblastic leukemia (DS-ALL). These leukemias are exclusively of the B lymphoid precursor phenotype and occur in a similar age to “common” sporadic ALLs with the striking absence of infant ALL. Recent studies reveal that DS-ALLs are heterogeneous and differ from sporadic ALLs. Only about a fifth of DS-ALLs carry the common cytogenetic aberrations typical to childhood ALL. Genomic rearrangements leading to the expression of a cytokine receptor, CRLF2, are detected in 60% of DS-ALL in comparison with up to 10% of sporadic ALLs. CRLF2 heterodimerizes with Interleukin 7 receptor-α (IL7R) to form the receptor to thymic stromal lymphopoietin (TSLP). This receptor is usually present in macrophages, dendritic cells, and some T lymphocytes and participates in allergic and inflammatory processes. The aberrant expression of the TSLP receptor is DS-ALL (and sporadic ALL) is often associated with additional mutations that cause constitutive activation of the downstream JAK-STAT and mTOR growth signaling pathways. These are either lymphoid specific activating mutations of JAK2 or JAK1 or mutations in CRLF2 or IL7R that cause ligand-independent receptor dimerization. The role of the trisomy in selecting these somatic abnormalities is presently unknown. Clinically, the prognosis of DS-ALL is inferior to sporadic ALL mainly because of increased treatment toxicity. However, recent data suggest that the inferior outcome may also be related to the genetic properties of the leukemic cells and that excessive chemotherapy dose reduction may not be appropriate for these patients. Therefore increased vigilance for infectious complications and optimal supportive care are required during periods of intensive chemotherapy. The common activation of the TSLP signaling pathway in DS-ALLs suggests a future for targeted therapy with JAK and/or mTOR inhibitors. Importantly, research of DS-ALL has proven relevant for the general patient population with ALL, as somatic mutations in the TSLP pathway have been discovered in children and adults with sporadic ALL. A major research challenge is the elucidation of the roles of constitutional and somatic trisomy 21 in leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

Blood ◽  
2012 ◽  
Vol 120 (15) ◽  
pp. 3039-3047 ◽  
Author(s):  
Kevin Y. Urayama ◽  
Anand P. Chokkalingam ◽  
Catherine Metayer ◽  
Xiaomei Ma ◽  
Steve Selvin ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Acute Lymphoblastic Leukemia ◽  
Immune Modulation ◽  
Lymphoblastic Leukemia ◽  
Human Leukocyte ◽  
Potential Interaction ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All ◽  
Increased Risk ◽  
Ear Infections

Abstract The human leukocyte antigen (HLA) genes are candidate genetic susceptibility loci for childhood acute lymphoblastic leukemia (ALL). We examined the effect of HLA-DP genetic variation on risk and evaluated its potential interaction with 4 proxies for early immune modulation, including measures of infectious exposures in infancy (presence of older siblings, daycare attendance, ear infections) and breastfeeding. A total of 585 ALL cases and 848 controls were genotyped at the HLA-DPA1 and DPB1 loci. Because of potential heterogeneity in effect by race/ethnicity, we included only non-Hispanic white (47%) and Hispanic (53%) children and considered these 2 groups separately in the analysis. Logistic regression analyses showed an increased risk of ALL associated with HLA-DPB1*01:01 (odds ratio [OR] = 1.43, 95% CI, 1.01-2.04) with no heterogeneity by Hispanic ethnicity (P = .969). Analyses of DPB1 supertypes showed a marked childhood ALL association with DP1, particularly for high-hyperdiploid ALL (OR = 1.83; 95% CI, 1.20-2.78). Evidence of interaction was found between DP1 and older sibling (P = .036), and between DP1 and breastfeeding (P = .094), with both showing statistically significant DP1 associations within the lower exposure categories only. These findings support an immune mechanism in the etiology of childhood ALL involving the HLA-DPB1 gene in the context of an insufficiently modulated immune system.

Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4257-4264 ◽  
Author(s):  
Smita Bhatia ◽  
Harland N. Sather ◽  
Olga B. Pabustan ◽  
Michael E. Trigg ◽  
Paul S. Gaynon ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Brain Tumors ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Malignant Neoplasms ◽  
Childhood All ◽  
Second Neoplasms ◽  
Increased Risk ◽  
The Impact

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.

scholarly journals Does Body Mass Index (BMI) during Maintenance Influence Relapse Risk in Children with Acute Lymphoblastic Leukemia (ALL)? Results from COG-AALL03N1

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 213-213
Author(s):  
Aman Wadhwa ◽  
Yanjun Chen ◽  
Lindsey Hageman ◽  
Anna Hoppmann ◽  
Anne L Angiolillo ◽  
...  
Keyword(s):  
Morbid Obesity ◽  
Maintenance Therapy ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Morbidly Obese ◽  
Red Cell ◽  
Childhood All ◽  
Relapse Risk ◽  
Increased Risk ◽  
Race Ethnicity

Abstract Introduction: Higher BMI at ALL diagnosis is associated with an increased risk of post-induction residual leukemia (Orgel, Blood 2014) and relapse (Butturini, JCO 2007). However, children may experience significant changes in BMI during the pre-maintenance phases of ALL treatment (Withycombe, Pediatr Blood Cancer 2009), necessitating an examination of the association between BMI during maintenance and relapse risk. We hypothesized that higher BMI during maintenance would be associated with a greater risk of relapse. We also explored the association between BMI and red cell thioguanine (TGN) levels to understand whether BMI-associated variations in TGN biodistribution explained the BMI-relapse association. Methods: We used data from COG-AALL03N1 (primary aim was 6MP adherence) to examine the association between BMI during maintenance and relapse risk. Eligibility for enrollment on AALL03N1 included age ≤21y at ALL diagnosis and receiving maintenance therapy in first remission. The current analysis was limited to patients with wild-type thiopurine methyltransferase genotype. BMI (exposure variable) was calculated as sex- and age-based percentile per CDC normative data, and operationalized as normal/underweight [&lt;85%ile], overweight/obese [85-98%ile] and morbidly obese [≥99%ile]). Hazard of relapse (any site) was estimated using multivariable proportional subdistributional hazards regression after adjusting for age at study enrollment, sex, race/ethnicity, NCI risk group, cytogenetics, 6MP dose intensity (6MPDI), and time from initiation of maintenance. We compared fitted means of red cell TGN levels by BMI groups after adjusting for age at enrollment, sex, race/ethnicity, 6MPDI and time from initiation of maintenance using generalized estimated equations. The association between BMI and relapse risk, as well as between BMI and TGN levels, was also examined in a sub-cohort of patients with available 6MP adherence. Results: The sociodemographic and disease characteristics of the 676 study participants are summarized in the Table. Median BMI%ile was 88.5 (range, 0-100); normal/underweight: 43%, overweight/obese: 45%, and morbidly obese: 12%. As shown in the Figure, cumulative incidence of relapse at 2y from start of maintenance therapy was significantly greater among patients with morbid obesity (11.9±4.3%) when compared to those who were overweight/obese (5.4±1.6%) and underweight/normal weight (4.1±1.4%). After adjusting for the variables listed above, we found that patients with morbid obesity had a 3.2-fold greater hazard of relapse (95%CI=1.4-7.5, P=0.008) when compared to patients who were normal/underweight. After adjusting for age at enrollment, sex, race/ethnicity, 6MPDI, and time from initiation of maintenance, patients with morbid obesity had lower mean red cell TGN levels compared to normal/underweight patients (mean difference: -27.2±7.4 pmol/8 x 10 8 erythrocytes, P=0.0002). However, inclusion of TGN in the model did not alter the association between BMI and hazard of relapse (HR=3.8, 95%CI, 1.6-9.0, P=0.003). These findings did not change after adjusting for 6MP adherence in the sub-cohort with available adherence data (n=435). Conclusion: Morbid obesity during maintenance for childhood ALL is associated with relapse as well as lower systemic exposure to 6MP. However, lower TGN levels do not explain the relation between BMI and relapse risk. Therefore, there is a need to understand the mechanism of the relation between morbid obesity during maintenance and relapse risk in children with ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals NUDT15 Variants Confer High Incidence of Secondary Malignancies of ALL in Children

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2751-2751
Author(s):  
Masanori Yoshida ◽  
Kazuhiko Nakabayashi ◽  
Aiko Sato-Otsubo ◽  
Shinichi Tsujimoto ◽  
Kaoru Yoshida ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Sensitivity ◽  
Late Complications ◽  
Buccal Swab ◽  
Malignant Neoplasms ◽  
Childhood All ◽  
Increased Risk ◽  
Functional Alleles

Background: Secondary or subsequent malignant neoplasms (SMNs) are one of the most serious late complications in children and adolescents after treatment for acute lymphoblastic leukemia (ALL). Several studies have reported that excess dosing of 6-mercaptopurine (6-MP) therapy and polymorphisms of 6-MP metabolizing enzyme coding gene might influence the risk of SMNs. Recently, nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants have been identified as a cause of high sensitivity to 6-MP, which reflects a high sensitivity to 6MP in East Asians. Therefore, we investigated an association between NUDT15 genotype and incidence of SMNs in pediatric ALL. Methods: Germline samples including bone marrow samples, peripheral blood samples and buccal swab samples during remission were obtained from 13 cases who suffered from SMN after childhood ALL. The prevalence of major NUDT15 non-functional alleles (*2 and *3), which is categorized intermediate or poor metabolizer of 6-MP in Clinical Pharmacogenetics Implementation Consortium Guideline (Relling M et al. Clin Pharmacol Ther 2019), was evaluated by using Sanger sequencing and/or whole exome sequencing. The NUDT15 variants prevalence in SMN patients with primary ALL was compared to those without SMN, who were registered in the TCCSG L04-16 study, which was conducted by the Tokyo Children's Cancer Study Group (TCCSG). Results: Patients' profiles and NUDT15 genotypes were summarized in table 1. Median ages at diagnoses of ALL and SMNs were 4 (1-15) and 13 (5-44) years, respectively. Median duration between ALL and SMNs was 8 (1-30) years. SMNs included acute myeloblastic leukemia (AML) / myelodysplastic syndrome (MDS) (n = 8), brain tumor (n = 1), basal cell carcinoma (n = 1), bladder cancer (n = 1), Ewing sarcoma (n = 1) and osteosarcoma (n = 1). Among the 13 SMN cases, six patients (46.2%) possessed NUDT15 non-functional alleles. The SMNs of these cases included AML / MDS (n = 4), bladder cancer (n = 1) and osteosarcoma (n = 1). Among them, 3 patients, whose SMNs were AML, bladder cancer and osteosarcoma, were treated with radiation therapy against primary ALL. All NUDT15 genotypes were heterozygous variants (3 were *1/*2 and 3 were *1/*3) and seemed to be intermediate metabolizers. In patients without known SMNs in TCCSG ALL L04-16 cohort study, 73 of 437 (16.7%) possessed NUDT15 non-functional alleles. Three of them had bi-allelic variants (2 cases were *3/*3, 1 case was *2/*3), and the others were all heterozygous. The prevalence of NUDT15 non-functional alleles was significantly higher in SMNs compared to that of non-SMN cases (P = 0.012). Conclusion: Our study indicated the NUDT15 hypomorphic variant alleles could be a risk of SMNs after ALL treatment with 6-MP. NUDT15 heterozygotic variants carriers are generally tolerable of 6-MP, and are usually treated with normal or slightly low-dose of 6-MP. However, our results suggested that standard adjustment of 6-MP in maintenance therapy might cause potential overdose of 6-MP for cases with NUDT15 variants, leading to increased risk of SMNs. To certify it, a higher number of study samples and somatic samples analysis of 6-MP induced SMNs are required. To obtain the best long-term event-free survival probability, it might be necessary to reduce the risk of SMNs development without compromising therapeutic effect by further optimal adjustment of 6-MP dose (or alternative agents). Disclosures No relevant conflicts of interest to declare.

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