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Therapeutic advances over recent decades have significantly improved cure rates for pediatric cancers. However, this success has come with a growing concern: The emergence of second primary tumors in childhood cancer survivors.

A recent study led by Spanish researchers and published in Cancer Discovery shed new light on the molecular causes of these second tumors. The team identified lasting genomic changes — so-called mutational signatures — left by chemotherapy, which may play a role in the development of subsequent malignancies.

Although pediatric cancers — often referred to as developmental cancers — represent a small percentage of all cancer cases, they affect an estimated 400,000 children worldwide each year. The occurrence of two unrelated cancers in a single child is rare, but when it happens, understanding the underlying causes offers new insights into cancer initiation mechanisms. These findings could improve early diagnosis and inform future treatment and surveillance strategies in pediatric oncology.

Contributing Factors

The development of second tumors is influenced by several factors. These include the type and intensity of treatment received during the first cancer, as well as the age at initial diagnosis, genetic predisposition, and the biologic characteristics of the original tumor.

“Although we know that chemotherapy administered years earlier is associated with second tumor development, we cannot always determine whether it was caused directly by the mutagenic action of the drugs,” explained lead author Mònica Sánchez-Guixé, PhD. “What we do know is that these therapies increase the mutational burden in the child’s body, which raises important questions about their long-term health impact.”

Most Common Second Tumors

Although relatively rare, second malignancies represent a serious long-term complication of pediatric cancer treatment. According to recent clinical data and literature reviews, these second tumors tend to fall into two main categories: Hematologic neoplasms and solid tumors.

Among hematologic cancers, acute myeloid leukemia and myelodysplastic syndromes are the most commonly reported. These are strongly linked to prior chemotherapy and radiotherapy, particularly exposure to epipodophyllotoxins and alkylating agents. Lymphomas, both Hodgkin and non-Hodgkin types, are also observed in survivors previously treated for other cancers.

In terms of solid tumors, the most frequently seen in childhood cancer survivors include breast cancer, thyroid cancer, and osteosarcomas. Other second cancers such as lung, colorectal, melanoma, and central nervous system tumors have also been documented, though less commonly. Less frequent still — but reported — are head and neck cancers, bladder cancer, prostate cancer, and certain neuroendocrine tumors.

Mechanisms Involved

Using advanced whole genome sequencing techniques, the research team analyzed how second primary cancers developed in four pediatric patients previously treated for cancer.

Their findings pointed to three primary mechanisms underlying the development of second tumors in childhood:

1. Mutagenesis induced by cancer therapies
2. A common embryonic origin for both tumors
3. Independent, unrelated mutational events

Chemotherapy-Induced Mutational Signatures

The study highlighted that certain cytotoxic chemotherapies, especially platinum-based drugs and alkylating agents, leave behind distinct mutational signatures in non-tumor tissues. These alterations — including chromosomal deletions and translocations — can persist for years after treatment and significantly increase the risk for second malignancies.

In one of the cases studied, a child developed secondary acute myeloid leukemia 4 years after treatment for sarcoma. Genomic analysis revealed alterations consistent with chemotherapy-induced DNA damage. Across the cohort, chemotherapy-related mutational signatures were identified in approximately 25% of second tumors, particularly leukemias.

Importantly, the researchers found that the accumulation of these mutations in healthy tissues increased the risk for second neoplasms by 2.3 times. While a direct causal link cannot be established in all cases, the presence of treatment-specific genomic signatures suggests a meaningful role for prior therapy in the pathogenesis of second cancers.

Common Embryonic Origin

Another major mechanism identified was a shared embryonic origin. In approximately 25% of cases, the two cancers were traced back to somatic mutations acquired during early fetal development — often before the fifth week of gestation. Genomic sequencing revealed shared alterations between the tumors, indicating they derived from the same early progenitor cell.

These cases suggest defects in DNA repair pathways or key tumor suppressor genes, such as RB1, may predispose some children to multiple cancers. One illustrative case involved a child who developed two distinct brain tumors, diagnosed 8 years apart, both arising from an early RB1 mutation.

The study underscored that approximately 75% of second tumors in children are attributable to either iatrogenic causes (treatment-induced) or embryologic factors. These findings are prompting oncologists and researchers to reconsider long-term surveillance strategies and treatment approaches for pediatric cancer survivors, particularly those with prolonged remission periods who later develop new malignancies.

Independent Oncogenic Events

In 50% of the cases analyzed, the second tumors did not share a genetic relationship with the primary tumor, indicating that they arose from independent mutational processes. In two of the four detailed cases, the tumors displayed distinct mutation profiles, likely acquired at different stages of prenatal development, particularly during organogenesis, and unrelated to prior cancer treatments.

These findings suggested that random DNA replication errors, unidentified environmental exposures, or inherited predispositions may contribute to the emergence of secondary neoplasms. The study authors proposed that early failures in DNA repair mechanisms could increase the likelihood of independent tumorigenic events.

This insight underscores the biologic complexity of pediatric cancer and highlights the importance of applying advanced genomic sequencing techniques to distinguish the origin and etiology of each tumor.

Cross-Cutting Findings

One of the study’s most important contributions is the identification of temporal mutational signatures, enabling researchers to estimate the timing of tumor initiation using molecular clock analysis. This methodology provides new clarity on the sequence and origin of secondary malignancies.

In addition, the research identified mutations in key cancer-associated genes — including TP53, NF1, and ALK — which appear to act as shared risk factors across multiple cancer types. These discoveries open new possibilities for targeted and personalized therapies in pediatric oncology.

Although the study was based on cases from Spain, its conclusions are consistent with data from global registries, such as the Childhood Cancer Survivor Study in the United States, which reports similar patterns in the occurrence of second malignancies among childhood cancer survivors.

The research also highlighted several clinical challenges, including the urgent need to implement surveillance strategies tailored to individual mutational profiles. Such approaches aim to limit cumulative genetic damage and facilitate early detection of second cancers. Additionally, the study emphasized the potential of developing less mutagenic chemotherapies and using liquid biopsies to monitor posttreatment genomic evolution — advances that could significantly improve long-term outcomes for pediatric cancer survivors.

This story was translated from El Medico Interactivo using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.