Therapy-related mutational signatures in subsequent neoplasms among survivors of childhood cancer
Menée à partir de l'analyse génomique d'échantillons tumoraux prélevés sur 160 patients atteints d'un méningiome, d'une tumeur thyroïdienne ou d'une tumeur mammaire après le traitement d'un premier cancer diagnostiqué pendant l'enfance, cette étude identifie des signatures mutationnelles liées à ce traitement
Childhood cancer survivors have heightened risk of developing subsequent neoplasms (SNs) related to therapy. We analyzed whole-genome, exome and RNA sequencing of 200 breast, meningioma, and thyroid SNs, which developed a median of 26.4 years after childhood cancer, among 160 survivors. Meningioma and thyroid SNs were enriched for driver gene rearrangements compared to de novo tumors, including NF2-disrupting alterations and kinase fusions potentially induced by radiation. Radiation correlated with increased insertion-deletion signature ID5. Nitrogen mustard treatment correlated with elevated “flat” signature SBS5 in breast and meningioma SNs; in vitro, these agents caused an unresolved flat signature associated with multiple flat COSMIC signatures. In meningioma, platinum therapy correlated with NF2 splice-site variants. Analysis of 19 multi-sample survivors revealed intrapatient heterogeneity in meningioma, including clonally independent tumors. These results demonstrate the long-term impact of childhood cancer treatment on the genomes of SNs developing in adulthood, which may guide SN treatment and prevention.
Cancer Discovery , article en libre accès, 2026