We identified germline single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL) and its subtypes. Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed (P<1×10 −5 ) between a pediatric ALL population (n=317) and non-ALL controls (n=17,958). Six of these SNPs differed (P≤0.05) in allele frequency among four ALL subtypes. Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P=1.4×10 −15 , odds ratio[OR]=1.91; rs10994982, P=5.7×10 −9 , OR=1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P=1.62 ×10 −5 , OR=2.17; rs10994982, P=0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n=124 children with ALL) (P=0.003 and P=0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline genomic variations affect susceptibility to and characteristics of specific ALL subtypes.Pediatric acute lymphoblastic leukemia (ALL) comprises biologically and clinically diverse subtypes. Somatically acquired genetic aberrations in ALL lymphoblasts are prognostic and can guide risk-directed therapy. 1 However, the extent to which germline variation contributes to susceptibility to ALL, to the acquisition of genetic aberrations that define ALL subtypes, and perhaps to the response to drug therapy among subtypes, is unknown. Candidate gene approaches have identified inherited polymorphisms in loci that may contribute to susceptibility to ALL, including the multidrug resistance gene ABCB1/MDR1, methylenetetrahydrofolate reductase (MTHFR), the glutathione-S-transferases as well as cellcycle inhibitor and DNA mismatch repair genes. 2-7 Lacking, however, are genome-wide studies that assess how inherited variation contributes to the development of ALL. Therefore, we conducted a genome-wide association study to identify germline single nucleotide polymorphisms (SNPs) in children with newly diagnosed ALL that may be associated with the development of ALL and with specific ALL subtypes.We first identified SNPs whose allele frequency differed between a discovery cohort of 317 children of European descent with ALL and 17,958 individuals of European descent without ALL from three independent control groups ( Supplementary Fig. 1). After applying quality control criteria, we evaluated 307,944 germline SNPs. Eighteen SNPs differed in allele frequency (using P-value thresholds specified in Supplementary Fig. 1) between patients with ALL and non-ALL controls ( We next compared the allele frequency of these 18 SNPs among four major ALL subtypes (Bother, B-hyperdiploid, t(12;21)/ETV6-RUNX1, and T-cell ALL) in the discovery cohort and found that six SNPs distinguished among the subtypes (P≤0.05) ( Table 2). The two ARID5B SNPs (rs10821936 and rs10994982) distinguished B-hyperdiploid ALL from all ...

The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which mercaptopurine doses are individualized on the basis of TPMT genotype.

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EDIATRIC ACUTE LYMPHOBLAStic leukemia (ALL) cure rates have increased from less than 10% in the 1960s to more than 80% today. Such advancement was partly derived from the identification of presenting clinical features (eg, molecular subtype, leukocyte count, age) associated with treatment outcome and subsequent implementation of risk-adapted therapy. 1,2 The assessment of decreasing disease bur-den in response to therapy by sequential monitoring of minimal residual disease (MRD) status has n o w b e e n i n t e g r a t e d i n t o r i s k stratification. [3][4][5] Minimal residual dis-See also Patient Page.

There is evidence that testing for human papillomavirus (HPV) E6/E7 mRNA is more specific than testing for HPV DNA. A retrospective study was carried out to evaluate the performance of the PreTect HPV-Proofer E6/E7 mRNA assay (Norchip) as a triage test for cytology and HPV DNA testing. This study analyzed 1,201 women, 688 of whom had a colposcopy follow-up and 195 of whom had histology-confirmed high-grade intraepithelial neoplasia or worse (CIN2؉). The proportion of positive results and the sensitivity and specificity for CIN2؉ were determined for HPV mRNA in comparison to HPV DNA and cytology. All data were adjusted for follow-up completeness. Stratified by cytological grades, the HPV mRNA sensitivity was 83% (95% confidence interval [CI] ‫؍‬ 63 to 94%) in ASC-US (atypical squamous cells of undetermined significance), 62% (95% CI ‫؍‬ 47 to 75%) in L-SIL (low-grade squamous intraepithelial lesion), and 67% (95% CI ‫؍‬ 57 to 76%) in H-SIL (high-grade squamous intraepithelial lesion). The corresponding figures were 99, 91, and 96%, respectively, for HPV DNA. The specificities were 82, 76, and 45%, respectively, for HPV mRNA and 29, 13, and 4%, respectively, for HPV DNA. Used as a triage test for ASC-US and L-SIL, mRNA reduced colposcopies by 79% (95% CI ‫؍‬ 74 to 83%) and 69% (95% CI ‫؍‬ 65 to 74%), respectively, while HPV DNA reduced colposcopies by 38% (95% CI ‫؍‬ 32 to 44%) and by 15% (95% CI ‫؍‬ 12 to 19%), respectively. As a HPV DNA positivity triage test, mRNA reduced colposcopies by 63% (95% CI ‫؍‬ 60 to 66%), having 68% sensitivity (95% CI ‫؍‬ 61 to 75%), whereas cytology at the ASC-US؉ threshold reduced colposcopies by 23% (95% CI ‫؍‬ 20 to 26%), showing 92% sensitivity (95% CI ‫؍‬ 87 to 95%). In conclusion, PreTect HPV-Proofer mRNA can serve as a better triage test than HPV DNA to reduce colposcopy referral in both ASC-US and L-SIL. It is also more efficient than cytology for the triage of HPV DNA-positive women. Nevertheless, its low sensitivity demands a strict follow-up of HPV DNA positive-mRNA negative cases.

The lipid partition constant and volume of distribution can likely be used to predict the efficacy of lipid infusion in reversing the cardiac toxicity induced by anesthetics or other medications.

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