Epidemiology of childhood germ cell tumors (GCT): epigenome-wide methylation, differential MiRNA expression, and catchment quality of the CCRN

Abstract

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.