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Second hits may or may not be sufficient for neoplastic transformation. Here we performed whole-genome and whole-exome sequencing on 479 tissue biopsies from a child with neurofibromatosis type 1, a multisystem cancer-predisposing syndrome mediated by constitutive monoallelic\n                    <jats:italic>NF1<\/jats:italic>\n                    inactivation. We identified multiple independent\n                    <jats:italic>NF1<\/jats:italic>\n                    driver variants in histologically normal tissues, but not in 610 biopsies from two nonpredisposed children. We corroborated this finding using targeted duplex sequencing, including a further nine adults with the same syndrome. Overall, truncating\n                    <jats:italic>NF1<\/jats:italic>\n                    mutations were under positive selection in normal tissues from individuals with neurofibromatosis type 1. We demonstrate that normal tissues in neurofibromatosis type 1 commonly harbor second hits in\n                    <jats:italic>NF1<\/jats:italic>\n                    , the extent and pattern of which may underpin the syndrome\u2019s cancer phenotype.\n                  <\/jats:p>","DOI":"10.1038\/s41588-025-02097-2","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T05:02:39Z","timestamp":1740459759000},"page":"515-521","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Cancer-independent somatic mutation of the wild-type NF1 allele in normal tissues in neurofibromatosis type 1"],"prefix":"10.1038","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4306-0102","authenticated-orcid":false,"given":"Thomas R. 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Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880\u2013886 (2015).","journal-title":"Science"},{"key":"2097_CR2","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1038\/s41586-019-1672-7","volume":"574","author":"H Lee-Six","year":"2019","unstructured":"Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532\u2013537 (2019).","journal-title":"Nature"},{"key":"2097_CR3","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/s41586-021-03822-7","volume":"597","author":"L Moore","year":"2021","unstructured":"Moore, L. et al. The mutational landscape of human somatic and germline cells. Nature 597, 381\u2013386 (2021).","journal-title":"Nature"},{"key":"2097_CR4","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1126\/science.aba8347","volume":"370","author":"ARJ Lawson","year":"2020","unstructured":"Lawson, A. R. J. et al. 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D.H. provides consultancy to AstraZeneca\/MedImmune, Alexion Pharmaceuticals, Bayer, Biodexa, Roche\/Genentech and Novartis, as well as expert testimony to AstraZeneca and Novartis, and his expenses are covered by Alexion Pharmaceuticals, Boehringer Ingelheim, Roche\/Genentech and Novartis. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}