Childhood cancers tend to be relatively simple in tumor genetic and epigenetic terms, reflecting their short latency of formation their identity as a misappropriation of normal tissue developmental growth pathways. The relatively few identified genetic susceptibility alleles are concentrated in developmental transcription factors and cell cycle genes, and tumor genetic and epigenetic changes tend to disrupt the same genes as found in genome-wide association studies. We will focus our discussion on the most frequent and the most studied childhood cancer, childhood leukemia, and on these topics: (i) the role of fetal tumor genetic and epigenetic alterations in identification of specific risk factors affecting in time windows of development (ii) the role of immune development and infection in cancer induction, and (iii) the impact of genetic variants that induce susceptibility to subtypes of cancer in specific populations.

The only bona fide causes of childhood leukemia are ionizing radiation and certain genetic predisposition and susceptibility alleles. Current progress in defining unrecognized causal pathways is being made by defining cancer in cytogenetic and epigenetic terms. As an example, chemical carcinogens (cigarette smoke, paints, solvents) are linked to leukemias with t(12;21) TEL-AML1 translocations, which have a prenatal origin. In genetic susceptibility terms, specific alleles (ARID5B, PIP4K2A) are associated leukemia with high hyperdiploidy.

While leukemia has long been linked to exposure to infectious agents, our current understanding implicates an interaction between immune development and response to early infections. We will present data showing that children who contract leukemia may be born with a congenital immune defect causing them to react to infections more strongly, resulting in damage to hematopoietic precursors and increased leukemia risk. Recognition of such immune defects, combined with identification of preleukemic mutations and genetic susceptibility markers, provides a likely roadmap for future efforts at early detection or risk stratification. Such an approach can lead to prevention efforts, which might involve immunologic modifications for risk reduction along with screening for appropriate genetic and epigenetic mutations.

Citation Format: Joseph L. Wiemels. Childhood cancer: Effects of genetic susceptibility and exposures to environmental agents. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr PL02-01.