Diagnosing cancer in a baby or young child raises profound questions, especially since the disease is relatively uncommon compared to adults. Pediatric cancers differ fundamentally from those seen later in life, as they are rarely connected to long-term lifestyle choices or chronic environmental exposures. The underlying causes are much more biological, centering on errors in development, growth, and inherited genetics. Understanding these differences shifts the focus from external risk factors to internal, developmental mechanisms occurring before or shortly after birth.
The Role of Fetal Development
Many childhood cancers originate from mistakes during the rapid cell division and differentiation of the fetal period or early infancy. These malignancies are often characterized by their primitive, embryonic nature, arising from progenitor cells that failed to mature into specialized tissue. This process is described as a disease of dysregulated development, where normal tissue formation is derailed by an early genetic error.
The resulting tumors, known as embryonal tumors, include neuroblastoma, retinoblastoma, hepatoblastoma, and Wilms tumor, which are rarely encountered in adults. Neuroblastoma, the most frequent solid tumor in infants, is believed to begin developing in the first trimester from sympathetic nervous system progenitor cells that do not fully differentiate. This highlights the vulnerability of “developmental plasticity,” where cells are highly active and prone to errors.
Abnormal growth is often initiated by an “oncogenic hit,” which is a mutation or chromosomal change occurring in an immature cell. This initial change creates a population of pre-cancerous cells that survive and continue to divide. For some leukemias, the first oncogenic event is detectable in the umbilical cord blood of newborns years before the disease manifests clinically. This evidence points to a prenatal origin for nearly half of all childhood cancers, demonstrating that the foundation for malignancy is laid in utero.
Inherited Genetic Predispositions
A small, but significant, percentage of pediatric cancers are directly linked to inherited genetic material, known as germline mutations. These mutations are passed down from a parent and are present in every cell of the child’s body from conception. Studies suggest that approximately 8 to 10% of pediatric cancer patients have a pathogenic germline mutation in a known cancer predisposition gene.
These inherited conditions typically involve defects in genes responsible for DNA repair or tumor suppression. This means the child begins life with a compromised mechanism for preventing cancer. For example, Li-Fraumeni syndrome is caused by a mutation in the TP53 gene. This syndrome drastically increases the lifetime risk of developing various cancers, including sarcomas and brain tumors, often at a very young age.
Another specific example is the RB1 gene mutation, which is linked to retinoblastoma, a tumor of the eye. Individuals who inherit one mutated copy of RB1 are highly susceptible to developing retinoblastoma, often in both eyes. This mechanism follows the “two-hit hypothesis,” where the inherited mutation (the first hit) is followed by a spontaneous mutation (the second hit) in the remaining healthy gene copy to trigger cancer.
Spontaneous Early-Life Mutations
The majority of genetic changes driving pediatric cancers are somatic mutations, which are random errors occurring after conception and are not inherited. These spontaneous mutations arise during the massive and rapid cell division required for growth and development in the fetus and infant. The sheer volume of cell replication in early life significantly increases the probability of a random error during DNA copying.
Somatic alterations can be small single-nucleotide changes or large chromosomal rearrangements, such as translocations that fuse two different genes. The types of mutations seen in pediatric tumors tend to be less numerous than those in adult cancers, but they often involve genes that regulate cell growth and differentiation.
A hypothesis suggests that “developmental mutators” are at play. These are normal genomic processes active during development that accidentally promote specific somatic mutations. For instance, the RAG1/2 DNA recombinase, essential for developing the immune system, can inadvertently cause chromosomal rearrangements that lead to certain types of leukemia and lymphoma. These random errors in progenitor cells create a cancerous clone that proliferates during infancy.
The Influence of Environmental Factors
Unlike most adult cancers, where lifestyle and long-term environmental exposures are major contributors, the causes of pediatric cancer are less clearly linked to external factors. The relatively short time a baby or child has been alive limits the opportunity for the accumulation of mutations from environmental carcinogens. Consequently, the dominant causes remain rooted in developmental and genetic mechanisms.
A few established links to external factors do exist, though they account for a small fraction of cases. Exposure to high doses of ionizing radiation is a proven risk factor for several pediatric cancers. Additionally, evidence suggests a weak association between prenatal or early-life exposure to certain pollutants, such as traffic-related air pollution and residential pesticides, and an increased risk of childhood leukemia and brain tumors. Specific infectious agents, such as the Epstein-Barr virus, are also known to be associated with certain types of lymphoma in children. Despite these few established connections, a large percentage of pediatric cancer cases remain idiopathic, meaning the specific cause is unknown. Researchers continue to investigate the subtle interplay between genetic predisposition and environmental triggers that might contribute to the development of these diseases.