Childhood cancer: genetic predisposition and mechanisms of origin

Abstract

Cancer is the main cause of death due to illness among children and adolescents in Brazil. Although approximately 80% of these patients survive over 5 years, this population is likely to suffer serious adverse effects because of the treatment received, like heart disease, lung problems, and subsequent tumors. Pediatric cancers present distinct biological profiles compared to adult tumors; they are intrinsically associated with the processes of organogenesis and growth and present a short-time window for their development, a fact that is reflected in the observed low frequency of somatic mutations. This scenario points to dissimilar mechanisms of origin between pediatric and adult tumors, emphasizing the role among children of germline mutations in the cancer predisposition, as well as epigenetic changes induced by environmental exposures. The prevalence and spectrum of mutations in genes related to cancer predisposition remain poorly explored in pediatric cancer. Additionally, few environmental factors were significantly associated with the genesis of childhood cancer. The Developmental Origins of Health and Disease (DOHAD) hypothesis proposes a model by which environmental exposures during pre / perinatal development would increase susceptibility to childhood cancer, not by inducing genetic mutations, but rather reprogramming the epigenome. The primary goal of this project is the investigation of the spectrum of genetic and epigenetic factors potentially associated with predisposition to pediatric cancer - (epi) germline mutations - and to tumor transformation or progression - (epi) somatic mutations. Two main subgroups will be studied using whole-exome sequencing and analysis of the DNA methylation profile: embryonal tumors, which present very early onset, and pediatric tumors occurring in patients exhibiting additional clinical signs/symptoms, such as dysmorphisms, congenital anomalies, and intellectual disability. We also propose a pilot study in a small cohort of patients generated by in vitro fertilization who developed childhood cancer to determine if there are methylome changes. (AU)