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<p>Cancer predisposition syndromes mediated by recessive cancer genes generate tumors via somatic variants (second hits) in the unaffected allele. 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 <i>NF1</i> inactivation. We identified multiple independent <i>NF1</i> 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 <i>NF1</i> 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 <i>NF1</i>, the extent and pattern of which may underpin the syndrome’s cancer phenotype.</p>

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Cancer-independent somatic mutation of the wild-type NF1 allele in normal tissues in neurofibromatosis type 1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月25日

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  • Thomas R. W. Oliver,
  • Andrew R. J. Lawson,
  • Henry Lee-Six,
  • Anna Tollit,
  • Hyunchul Jung,
  • Yvette Hooks,
  • Rashesh Sanghvi,
  • Matthew D. Young,
  • Timothy M. Butler,
  • Pantelis A. Nicola,
  • Taryn D. Treger,
  • Stefanie V. Lensing,
  • G. A. Amos Burke,
  • Kristian Aquilina,
  • Ulrike Löbel,
  • Isidro Cortes-Ciriano,
  • Darren Hargrave,
  • Mette Jorgensen,
  • Flora A. Jessop,
  • Tim H. H. Coorens,
  • Adrienne M. Flanagan,
  • Kieren Allinson,
  • Inigo Martincorena,
  • Thomas S. Jacques,
  • Sam Behjati

摘要

Cancer predisposition syndromes mediated by recessive cancer genes generate tumors via somatic variants (second hits) in the unaffected allele. 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 NF1 inactivation. We identified multiple independent NF1 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 NF1 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 NF1, the extent and pattern of which may underpin the syndrome’s cancer phenotype.