Origins of Second Malignancies in Children and Mutational Footprint of Chemotherapy in Normal Tissues

Area of Science:

• Oncology
• Genetics
• Pediatrics

Background:

• Pediatric cancers are rare, and secondary malignancies in children without germline predisposition are exceptionally uncommon.
• Understanding the origins of these rare secondary cancers is crucial for improving long-term outcomes in childhood cancer survivors.

Purpose of the Study:

• To investigate the etiological origins of second malignancies in four pediatric cancer cases.
• To elucidate the distinct pathways leading to the development of secondary neoplasms in children.

Main Methods:

• Whole-genome sequencing and ultra-deep duplex sequencing of tumor and normal samples from four pediatric patients.
• Analysis of mutation profiles to identify distinct clonal origins and mutational signatures.

Main Results:

• Identified diverse origins for second neoplasms, including therapy-related acute myeloid leukemia and early embryonic mutations driving solid tumors.
• Demonstrated that platinum-based therapies induce mutations at a significantly higher rate than aging in normal tissues.
• Observed independent clonal divergence during embryogenesis as a cause for secondary tumors in two cases.

Conclusions:

• Childhood cancer survivors face complex risks for secondary malignancies with varied underlying mechanisms.
• Cytotoxic therapies, particularly platinum-based agents, contribute substantially to the mutational burden in normal tissues, posing long-term risks.
• Further research is needed to mitigate therapy-induced mutagenesis and improve surveillance for secondary cancers in pediatric survivors.