Origins of Second Malignancies in Children and Mutational Footprint of Chemotherapy in Normal Tissues
Menée à partir d'échantillons sanguins, d'échantillons de moelle osseuse, d'échantillons tumoraux et d'échantillons de tissus normaux prélevés sur 4 patients pédiatriques atteints d'un second cancer, cette étude examine l'origine du second cancer et met en évidence la présence de mutations liées aux sels de platine dans des tissus normaux
Pediatric cancers are rare diseases, and children without known germline predisposing conditions who develop a second malignancy during developmental ages are extremely rare. We present four such clinical cases and, through whole-genome and error-correcting ultra-deep duplex sequencing of tumor and normal samples, we explored the origin of the second malignancy in four children, uncovering different routes of development. The exposure to cytotoxic therapies was linked to the emergence of a secondary acute myeloid leukemia. A common somatic mutation acquired early during embryonic development was the driver of two solid malignancies in another child. In two cases, the two tumors developed from completely independent clones diverging during embryogenesis. Importantly, we demonstrate that platinum-based therapies contributed at least one order of magnitude more mutations per day of exposure than aging to normal tissues in these children.Using whole-genome and error-correcting ultra-deep duplex sequencing, we uncover different origins for second neoplasms in four children. We also uncover the presence of platinum-related mutations across 10 normal tissues of exposed individuals, highlighting the impact that the use of cytotoxic therapies may have on cancer survivors.
Cancer Discovery , article en libre accès, 2023