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<p>Aged normal tissues harbour cancer mutations predisposing to transformation. However, how different pro-oncogenic events in the human colon compare in frequency, behaviour and subsequent transformation risk remains unclear. Here, we analyse mutation hotspot regions in five colorectal cancer genes (<i>APC</i>, <i>KRAS</i>, <i>TP53</i>, <i>FBXW7</i> and <i>CTNNB1</i>) using targeted sequencing of 76,800 normal colonic glands from 56 patients. We show that cancer-driving mutations&#xa0;are present in all genes in histologically normal tissue. Reconstruction of clone dynamics reveals that <i>FBXW7</i> R465C mutations preferentially become fixed within the tissue, whereas <i>KRAS</i> G12 mutations strongly promote expansion. Modelling mutation order indicates that early loss of both <i>APC</i> copies increasingly favours an <i>APC</i>-first pathway with age, while <i>KRAS</i> activation is equally likely to initiate events in younger individuals. Spatial transcriptomics highlights phenotypic heterogeneity among <i>KRAS</i> mutant clones, with mixed lineage presentation observed only in&#xa0;a subset, a state linked to elevated transformation risk in other organs.</p>

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Clonal biases dictate availability of colonic cancer driver mutations for transformation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月16日

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  • Nefeli Skoufou-Papoutsaki,
  • Richard Kemp,
  • Sam Adler,
  • Kate Marks,
  • Anne-Claire Girard,
  • Shenay Mehmed,
  • Filipe C. Lourenço,
  • Elisa B. Moutin,
  • Rogier Ten Hoopen,
  • Edward Morrissey,
  • Douglas J. Winton,
  • David S. Tourigny

摘要

Aged normal tissues harbour cancer mutations predisposing to transformation. However, how different pro-oncogenic events in the human colon compare in frequency, behaviour and subsequent transformation risk remains unclear. Here, we analyse mutation hotspot regions in five colorectal cancer genes (APC, KRAS, TP53, FBXW7 and CTNNB1) using targeted sequencing of 76,800 normal colonic glands from 56 patients. We show that cancer-driving mutations are present in all genes in histologically normal tissue. Reconstruction of clone dynamics reveals that FBXW7 R465C mutations preferentially become fixed within the tissue, whereas KRAS G12 mutations strongly promote expansion. Modelling mutation order indicates that early loss of both APC copies increasingly favours an APC-first pathway with age, while KRAS activation is equally likely to initiate events in younger individuals. Spatial transcriptomics highlights phenotypic heterogeneity among KRAS mutant clones, with mixed lineage presentation observed only in a subset, a state linked to elevated transformation risk in other organs.