Browsing by Subject "Childhood cancer"

Now showing 1 - 5 of 5
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    Epidemiology of childhood germ cell tumors (GCT): epigenome-wide methylation, differential MiRNA expression, and catchment quality of the CCRN
    (2013-09) Musselman, Jessica
    Epidemiology of Childhood Germ Cell Tumors (GCT): Epigenome-Wide Methylation, Differential MiRNA Expression, and Catchment Quality of the CCRN Germ cell tumors (GCTs) represent a heterogeneous group of neoplasms classified together through a common precursor cell, the primordial germ cell. The etiology of GCTs is not well elucidated, although genetic and epigenetic pathways are implicated. In this dissertation, I completed three complementary projects to further our understanding of these tumors. Project 1: I performed an epi-genome wide analysis of methylation in a large sample of childhood GCT (n = 111) to assess methylation with respect to survival, time to recurrence, and tumor histology. A semi-supervised recursively partitioned mixture modeling (SS-RPMM) algorithm segregated the GCTs into four methylation classes. Class membership was not significantly associated with tumor histology (p=0.06) or survival (p = 0.23), but was associated with disease recurrence (p = .02). These findings provide a strong rationale for future studies of methylation in GCT. Project 2: Particular interest has been paid to the role of miRNA in cancer in recent years, including studies in adult testicular GCTs. I conducted an evaluation of miRNA in GCTs by tumor and patient subgroups. Six miRNAs were differentially expressed by tumor histology after correction for multiple comparisons. These findings could provide insights into potential new targeted therapies. Project 3: The Childhood Cancer Research Network was established to ameliorate some of the difficulties associated with the study of childhood cancer; however, the quality of catchment in the CCRN has not been evaluated. I used data from the NCI's Surveillance, Epidemiology, and End Results (SEER) program and the 2010 U.S. Census to determine the ascertainment completeness of GCT cases over a 3-year period. Overall, enrollment was much lower than expected, particularly in the 15-19 year age group. These results provide useful insight into the completeness of case ascertainment of childhood GCT in the CCRN.
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    The etiology of hematologic malignancies in children and adolescents: Pre- and postnatal factors.
    (2010-03) Linabery, Amy Marie DeVries
    Little is known about the etiology of most pediatric hematologic malignancies, although there is evidence for prenatal initiation of leukemogenesis for many cases. The current body of research, a series of three complementary studies, evaluated the potential for unbiased measurement of prenatal exposures through retrieval of existing biospecimens and examined associations between pre- and postnatal exposures and pediatric/adolescent leukemia. The first study assessed the feasibility of retrospective collection of residual neonatal blood spots (NBS) for 947 childhood/adolescent leukemia and lymphoma cases from state newborn screening programs nationwide. Biological mothers were also asked to complete self-administered questionnaires regarding prenatal exposures, personal and family history of atopic disease, and selected demographic factors. Overall, 37% of families provided consent for NBS release and 41% of mothers completed questionnaires. Consenting cases were born in 39 states and 46 NBS were obtained from 5 states (CA, NY, MI, TX, and WA). NBS storage/release policies are rapidly evolving; requests are pending in states involved in litigation (MN), reviewing policies (NJ), and reviewing this study (MA). Currently, population-based NBS studies can be conducted in a limited number of states; fortunately, most of these have large populations to provide reasonable pediatric case and control groups. In the second study, the largest of its kind, the association between self-reported prenatal vitamin supplementation and infant leukemia was examined, since folic acid is postulated to play a preventative role in the pathogenesis of childhood leukemia, particularly among ALL cases. After adjustment for race/ethnicity and income, there was little evidence supporting associations between periconceptional vitamin use (OR = 0.89, 95% CI: 0.64-1.24), use after knowledge of pregnancy (OR = 0.78, 95% CI: 0.48-1.28), or use in all periods (OR = 0.84, 95% CI: 0.62-1.14) and infant leukemia. These results may be attributable to high rates of folic acid supplementation in the study population, including personal vitamin use and national folic acid fortification programs implemented in the U.S. and Canada early in the study period. Atopic disease is hypothesized to be protective for several malignancies. In the third study, meta-analysis was performed to summarize and quantify the risk of acute leukemia associated with atopic disease in children and adolescents and to identify sources of heterogeneity in the existing literature. Inverse associations were observed for ALL and atopy overall (OR = 0.69, 95% CI: 0.54-0.89)), and for asthma (OR = 0.79, 95% CI: 0.61-1.02), eczema (OR = 0.74, 95% CI: 0.58-0.96), and hay fever (OR = 0.55, 95% CI: 0.46-0.66) examined separately. ORs for ALL differed across strata of study design, exposure data source, and latency period, indicating these factors impact study results. Although these results should be interpreted cautiously given the modest number of studies, substantial heterogeneity, and potential exposure misclassification, they are useful in designing future research.
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    Hereditary and inborn etiology of pediatric cancer
    (2012-06) Zierhut, Heather Ann
    The etiology of childhood cancer remains largely elusive. In rare cases, genetic mutations and environmental exposures such as radiation are known causes. For the vast majority of childhood cancer patients, there is no known cause for their disease. With an increasing number of childhood cancer survivors, the need to understand disease for patients and their families is becoming even more vital. This dissertation will describe three different investigations to understand the role of genetic or inborn factors play in the etiology of childhood cancer. The first study reviewed investigates family history in acute lymphoblastic leukemia (ALL) patients. Family history information can provide insight into the genetic (and/or shared environmental) basis of an illness. We investigated the association of family history of specific cancers and non-malignant diseases in one of the largest case-control studies of childhood ALL conducted to date. In this study, family history of cancer was not significantly more frequent among ALL cases compared to controls. The likelihood of family history of esophageal cancer was lower in ALL cases as compared to controls but the number of affected relatives was small in both groups and due to multiple comparisons performed in the statistical analysis may not be a true association. For selected non-malignant conditions, significant inverse associations with family history of allergic disease, food and drug allergy, rheumatoid arthritis and risk of ALL were observed. The second study reviewed focuses on the association of rib anomalies and childhood cancer. Congenital anomalies have been associated with childhood cancer syndromes in many large epidemiological studies using population based registries. This study sought to better understand and more robustly describe the association between childhood cancer and morphological defects of the ribs in a hospital-based case-control United States population. Our results indicate a modest but fairly robust association between rib anomalies (RA) and childhood cancer. RAs were associated with increased odds of the individual cancer types AML, renal tumors, and hepatoblastoma. The final study reviewed examines common genetic variation associated with pediatric osteosarcoma (OS). A small subset of individuals develop OS due to a hereditary predisposition syndrome such as Li Fraumeni, Retinoblastoma, or Rothmund-Thompson syndrome. Mutations in the TP53, RB, and RECQL4 genes are highly penetrant and can confer up to a 90% chance of developing OS. We hypothesized that single nucleotide polymorphisms (SNPs) in these genes, and those in the same pathways affect risk of OS less drastically. In this analysis, we conducted a case-parent triad study to examine main effects of DNA repair and metabolism genes in pediatric OS. We identified a nonsynonymous SNP in RECQL4 that was most associated with OS although not significantly after correction for multiple comparisons. No significant associations of DNA repair genes previously described were replicated in this study. The three studies described above provide insight into the family history, congenital anomalies, and genes involved in molecular pathways associated with childhood cancer.
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    Infertility and infertility treatment: childhood cancer and epigenetic risks.
    (2010-05) Puumala, Susan Elizabeth
    Although childhood cancer is rare, it can have a devastating impact on the children who develop it and their families. Just as in adults, cancer in children is comprised of many disease types. Since the window for exposure is quite limited in childhood cancer, exposures encountered in utero are likely to contribute to carcinogenesis. Thus, etiologic studies have focused on exposures that occur during pregnancy for cancers that arise early in life. Parental infertility and infertility treatment have been hypothesized as possible risk factors for childhood cancer. The link is suspected since many infertile couples may have specific genetic or epigenetic anomalies that could be passed on to their children, which in turn could lead to carcinogenesis. Infertility treatment occurs at or near conception and may persist for several days after conception, making it plausible for treatment to affect early embryo development. In addition, infertility or infertility treatment may alter epigenetic patterns in the developing embryo resulting in an increase risk of childhood cancer. All of these reasons suggest a need to examine infertility and its treatment further. Three related studies are combined in this thesis to examine the potential influence of infertility and infertility treatment on childhood cancer. The first two studies examined the potential link between infertility and its treatment and two specific childhood cancer diagnoses: infant leukemia and germ cell tumors (GCT). As these two diagnoses are quite rare, few previous studies have been performed to examine infertility or its treatment as a possible risk factor. Overall, no significant associations between infertility or its treatment and infant leukemia or childhood GCT were found. However, some notable subgroup associations were found in both studies. In infant leukemia, there was an increased risk of the rare MLL- subtype in children born to women not trying to conceive compared to those trying to conceive for less than one year for all types combined and for acute lymphoblastic leukemia (ALL). In contrast, there was a decreased risk of acute myeloid leukemia (AML) for children born to women who reported use of medication to help them become pregnant. In GCT, there was an increased risk for non-gonadal tumors in females born to women with at least two fetal losses. The final study examined DNA methylation as a potential mechanism by which assisted reproductive technology (ART) might influence the risk of childhood cancer. The data were consistent with no difference in methylation between groups at all loci for lymphocyte samples. Possible differences were found in buccal cell samples for two loci; IGF2 DMR0 and IGF2R. Subgroup analysis indicated potential lower methylation in those whose parents used ART for unexplained infertility. Correlation between lymphocyte and buccal cell samples was low for all loci. The combined results of all three studies indicate no increased risk of infant leukemia, pediatric germ cell tumors, or epigenetic disruptions in specific loci associated with Beckwith-Wiedemann syndrome and certain types of childhood cancer. While an association may still exist for different types of childhood cancer or methylation levels in other loci or tissues, these studies should reassure parents of children conceived through infertility treatment at least somewhat.
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    Physical activity in childhood cancer survivors
    (2014-08) Slater, Megan Elizabeth
    Background: Childhood cancer survivors (CCS) are at high risk of developing treatment-related late effects, including cardiovascular disease and diabetes, which can be exacerbated by inadequate physical activity (PA). Relationships between PA, physical fitness, and cardiometabolic risk factors in CCS have not been well described. Furthermore, active transportation, a specific domain of PA, has not been previously studied in CCS. The primary aims of this dissertation were to examine associations between PA/fitness and cardiometabolic risk factors and to identify active transportation behaviors and barriers in CCS.Methods: In Project 1, associations between PA and cardiometabolic risk factors were examined in 319 CCS and 208 sibling controls aged 9-18 years. In Project 2, associations between PA/fitness and cardiometabolic risk factors were examined in 119 adult CCS with a history of hematopoietic cell transplantation and 66 adult sibling controls. In Project 3, we recruited 158 adult CCS and 153 controls matched on age, sex, and location to complete a survey regarding active transportation behaviors and perceptions. Linear and logistic regression models accounting for correlation among siblings or matched participants were used to address research questions.Results: Higher levels of PA in CCS aged 9-18 (Project 1) and higher levels of endurance in adult CCS (Project 2) were associated with a favorable cardiometabolic profile. In Project 3, adult CCS engaged in similar levels of active transportation as controls despite perceiving greater health-related barriers. Marital/relationship status, planning/psychosocial barriers, and perceived neighborhood walkability were the strongest correlates of active transportation among CCS, while objective neighborhood walkability was the strongest correlate among controls.Conclusions: Findings suggest that efforts to increase PA and endurance in CCS may reduce the risk of future cardiovascular disease. Interventions might consider promoting active transportation as a moderate intensity PA option, since it appears to be as well accepted in CCS as in healthy adults. Such interventions will not be successful, however, without existing or improved pedestrian and bicycle infrastructure, safety, and access to local amenities. Additional research is needed to confirm results and explore the feasibility and efficacy of active transportation interventions in this population.