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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 with de novo tumors, including NF2-disrupting alterations and kinase fusions potentially induced by radiation. Radiation correlated with increased insertion\u2013deletion signature ID5. Nitrogen mustard treatment correlated with elevated \u201cflat\u201d signature SBS5 in breast and meningioma SNs; in vitro, these agents caused an unresolved flat signature associated with multiple flat signatures from the Catalogue of Somatic Mutations in Cancer. In meningioma, platinum therapy correlated with NF2 splice-site variants. Analysis of 19 multisample 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>This represents the most comprehensive genomic characterization of SNs from childhood cancer survivors to date, revealing the mutagenic impact of multiple therapies on the SN genome, including the potential impact of nitrogen mustards such as cyclophosphamide. These results may guide the optimization of future cancer treatment regimens to prevent SN development.<\/jats:p>\n                    <jats:p>See related commentary by Bertrums and van Boxtel, p. 1483<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0231","type":"journal-article","created":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T20:01:38Z","timestamp":1776628898000},"page":"1590-1610","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Therapy-Related Mutational Signatures in Subsequent Neoplasms among Survivors of Childhood Cancer"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5518-7800","authenticated-orcid":false,"given":"Samuel W.","family":"Brady","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02r3e0967","id-type":"ROR","asserted-by":"publisher"}],"name":"St. Jude Children\u2019s Research Hospital 1 Department of 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