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Impact of aberrant DNA methylation patterns including CYP1B1 methylation in adolescents and young adults with acute lymphocytic leukemia.

ABSTRACT: Aberrant promoter DNA methylation is a well-described mechanism of leukemogenesis within hematologic malignancies, including acute lymphoblastic leukemia (ALL). However, the importance of methylation patterns among the adolescent and young adult (AYA) ALL population has not been well established. DNA methylation of 18 candidate genes in 33 AYA ALL patients was analyzed at diagnosis and during treatment, to evaluate the frequency and clinical relevance of aberrant methylation in an AYA population treated on a uniform therapeutic regimen. Of 16 informative genes, there was a median of 6 methylated genes per AYA ALL patient. Correlations were identified between increasing number of methylated genes with male sex (P = 0.04), increased white blood cell (WBC) count (P = 0.04) and increased bone-marrow blast percentage (P = 0.04). Increasing age was associated with EPHA5 methylation (P = 0.05). Overall, patients experienced favorable outcomes with median survival that was not reached. On univariate analysis, methylation of CYP1B1 was associated with worse overall survival (HR 10.7, 95% CI 1.3-87.6, P = 0.03), disease-free survival (HR 3.7, 95% CI 1.1-9.2, P = 0.04) and correlated with decreased CYP1B1 gene expression. A significant incidence of methylation within the AYA ALL population was identified, with increased methylation associated with distinct clinicopathologic features including male gender and elevated WBC count. Our results suggest aberrant methylation among AYA patients is frequent, and may provide a common pathogenic mechanism. The inferior outcome identified with methylation of the cytochrome p450 gene CYP1B1, an enzyme involved in drug metabolism and steroid synthesis, warrants further investigation.

SUBMITTER: DiNardo CD

PROVIDER: S-EPMC3947930 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Impact of aberrant DNA methylation patterns including CYP1B1 methylation in adolescents and young adults with acute lymphocytic leukemia.

DiNardo C D CD Gharibyan V V Yang H H Wei Y Y Pierce S S Kantarjian H M HM Garcia-Manero G G Rytting M M

American journal of hematology 20130723 9

Aberrant promoter DNA methylation is a well-described mechanism of leukemogenesis within hematologic malignancies, including acute lymphoblastic leukemia (ALL). However, the importance of methylation patterns among the adolescent and young adult (AYA) ALL population has not been well established. DNA methylation of 18 candidate genes in 33 AYA ALL patients was analyzed at diagnosis and during treatment, to evaluate the frequency and clinical relevance of aberrant methylation in an AYA population ...[more]

PMID: 23757320

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Project description:ImportanceSafe opioid prescribing practices are critical to mitigate the risk of prescription opioid overdose in adolescents and young adults. However, studies that examine opioid prescribing patterns associated with prescription opioid overdose have mostly focused on older adults. The generalizability of these studies to adolescents and young adults is unclear.ObjectiveTo identify opioid prescribing patterns associated with prescription opioid overdose in adolescents and young adults.Design, setting, and participantsThis retrospective cohort study assessed privately insured patients aged 12 to 21 years with opioid prescription claims in the IBM MarketScan Commercial Claims and Encounters database between July 1, 2009, and October 1, 2017, and no cancer diagnosis. Data analysis was performed from January 1 to April 30, 2019.Main outcomes and measuresThe outcome was a treated opioid overdose as indicated by diagnosis codes. On the basis of days supplied, opioid prescription claims were converted to person-days (the unit of analysis) on which opioid exposure would occur if patients took medications as prescribed. Logistic regression with clustered SEs at the patient level was used to model the occurrence of overdose on a person-day as a function of daily opioid dosage category (<30, 30-59, 60-89, 90-119, or ≥120 morphine milligram equivalents), concurrent benzodiazepine use, and extended-release or long-acting opioid use. Regressions controlled for demographic characteristics, year, opioid use within 180 days, and comorbidities (mental health disorder, substance use disorder, and other chronic condition).ResultsA total of 2 752 612 patients (mean [SD] age at cohort entry, 17.2 [2.5] years; 1 451 918 [52.8%] female) participated in the study. Patients had 4 686 355 opioid prescription claims, corresponding to 21 605 444 person-days. Overdose occurred on 255 person-days among 249 patients (0.01% of the sample). Each increase in daily opioid dosage category was associated with higher overdose risk (adjusted odds ratio [AOR], 1.18; 95% CI, 1.05-1.31). Compared with no use, both concurrent benzodiazepine use (AOR, 1.83; 95% CI, 1.24-2.71) and extended-release or long-acting opioid use (AOR, 2.01; 95% CI, 1.16-3.46) were associated with increased overdose risk.Conclusions and relevanceThe findings suggest that when prescribing opioids to adolescents and young adults, practitioners could potentially mitigate overdose risk by using the lowest effective daily dosage, avoiding concurrent opioid and benzodiazepine prescribing, and relying on short-acting opioids. Findings are broadly consistent with prior opioid safety studies focused on older adults.

Project description:BackgroundFor adolescents and young adults (AYAs, aged 15-39 years) with cancer, metastatic disease at diagnosis is the strongest predictor of mortality, but its associations with age and sociodemographic factors are largely unexplored.MethodsUsing Surveillance, Epidemiology, and End Results Program data from 2000 to 2016, we collected incident cases of poor-prognosis metastatic cancer (5-year survival < 50%) and compared the proportion, incidence, time trends, and incidence rate ratios for race and ethnicity, sex, and socioeconomic status among AYAs, middle-aged adults (aged 40-64 years) and older adults (aged 65-79 years).ResultsFrom 2000 to 2016, a total of 17 210 incident cases of poor-prognosis metastatic cancer were diagnosed in AYAs, 121 274 in middle-aged adults, and 364 228 in older adults. Compared with older patients, the proportion of AYAs having metastatic disease was equivalent or substantially lower in nearly every site except stomach and breast cancers, which were statistically significantly higher for AYAs compared with middle-aged and older adults (stomach: 57.3% vs 46.4% and 39.5%; breast: 6.6% vs 4.4% and 5.6%, respectively; 2-sided P < .001 for all comparisons). Incidence rates rose significantly faster among AYAs for breast, stomach, and kidney cancers and among AYAs and middle-aged adults for colorectal cancer. Markedly higher incidence rate ratios were noted for AYA racial and ethnic minorities with breast, stomach, and especially kidney cancer, where only non-Hispanic Black AYAs were at considerably higher risk. For most sites, incidence rate ratios were higher among male patients and individuals of low socioeconomic status across age groups.ConclusionsFor most cancers, AYAs are not more likely to present with metastases than middle-aged and older adults. Further investigation is warranted for the disproportionate rise in incidence of metastatic breast, stomach, and kidney cancer among AYAs and their excess burden among AYA racial and ethnic minorities. The rising incidence of colorectal cancer among AYAs and middle-aged adults remains an additional concern.

Dataset Information

Impact of aberrant DNA methylation patterns including CYP1B1 methylation in adolescents and young adults with acute lymphocytic leukemia.

Publications

Impact of aberrant DNA methylation patterns including CYP1B1 methylation in adolescents and young adults with acute lymphocytic leukemia.

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