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<p>Most solid tumors harbor somatic mutations attributed to off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B). However, how APOBEC3A/B enzymes affect tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, multi-omics profiling of 309 lung cancers from smokers identifies two subtypes defined by low (<i>LAS</i>) and high (<i>HAS</i>) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and <i>KRAS</i> mutations; HAS for A3A-like mutagenesis and <i>TP53</i> mutations. Compared to LAS, HAS have older age at onset and high proportions of newly generated progenitor-like cells likely due to the combined tobacco smoking- and APOBEC3A-associated DNA damage and apoptosis. Consistently, HAS exhibit high expression of pulmonary healing signaling pathway, stemness markers, distal cell-of-origin, more neoantigens, slower clonal expansion, but no smoking-associated genomic/epigenomic changes. With validation in 184 lung tumor samples, these findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development.</p>

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APOBEC affects tumor evolution and age at onset of lung cancer in smokers

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月21日

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  • Tongwu Zhang,
  • Jian Sang,
  • Phuc H. Hoang,
  • Wei Zhao,
  • Jennifer Rosenbaum,
  • Kofi Ennu Johnson,
  • Leszek J. Klimczak,
  • John McElderry,
  • Alyssa Klein,
  • Christopher Wirth,
  • Erik N. Bergstrom,
  • Marcos Díaz-Gay,
  • Raviteja Vangara,
  • Frank Colon-Matos,
  • Amy Hutchinson,
  • Scott M. Lawrence,
  • Nathan Cole,
  • Bin Zhu,
  • Teresa M. Przytycka,
  • Jianxin Shi,
  • Neil E. Caporaso,
  • Robert Homer,
  • Angela C. Pesatori,
  • Dario Consonni,
  • Marcin Imielinski,
  • Stephen J. Chanock,
  • David C. Wedge,
  • Dmitry A. Gordenin,
  • Ludmil B. Alexandrov,
  • Reuben S. Harris,
  • Maria Teresa Landi

摘要

Most solid tumors harbor somatic mutations attributed to off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B). However, how APOBEC3A/B enzymes affect tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, multi-omics profiling of 309 lung cancers from smokers identifies two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations; HAS for A3A-like mutagenesis and TP53 mutations. Compared to LAS, HAS have older age at onset and high proportions of newly generated progenitor-like cells likely due to the combined tobacco smoking- and APOBEC3A-associated DNA damage and apoptosis. Consistently, HAS exhibit high expression of pulmonary healing signaling pathway, stemness markers, distal cell-of-origin, more neoantigens, slower clonal expansion, but no smoking-associated genomic/epigenomic changes. With validation in 184 lung tumor samples, these findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development.