Hereditary and inborn etiology of pediatric cancer

Abstract

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.