Scholarlink

<p>The extent to which exogenous sources, including cancer treatment, contribute to somatic evolution in normal tissue remains unclear. Here we used high-depth duplex sequencing<sup><CitationRef CitationID="CR1">1</CitationRef></sup> (more than 30,000× coverage) to analyse 168 cancer-free samples representing 16 organs from 22 patients with metastatic cancer enroled in the PEACE research autopsy study. In every sample, we identified somatic mutations (range 305–2,854 mutations) at low variant allele frequencies (median 0.0000323). We extracted 16 distinct single-base substitution mutational signatures, reflecting processes that have moulded the genomes of normal cells. We identified alcohol-induced mutation acquisition in liver, smoking-induced mutagenesis in lung and cardiac tissue, and multiple treatment-induced processes, which correlated with therapy type and duration. Exogenous sources, including treatment, underpinned, on average, more than 40% of mutations in liver but less than 10% of mutations in brain samples. Finally, we observed tissue-specific selection, with positive selection in tissues such as lung (<i>PTEN</i> and<i> PIK3CA</i>), liver (<i>NF2L2</i>) and spleen (<i>BRAF</i> and<i> NOTCH2</i>), and limited selection in others, such as brain and cardiac tissue. More than 25% of driver mutations in normal tissue exposed to systemic anti-cancer therapy, including in <i>TP53</i>, could be attributed to treatment. Immunotherapy, although not associated with increased mutagenesis, was linked to driver mutations in <i>PPM1D</i> and <i>TP53</i>, illustrating how non-mutagenic treatment can sculpt somatic evolution. Our study reveals the rich tapestry of mutational processes and driver mutations in normal tissue, and the profound effect of lifetime exposures, including cancer treatment, on somatic evolution.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Somatic evolution following cancer treatment in normal tissue

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月10日

查看全文
  • Oriol Pich,
  • Sophia Ward,
  • Andrew Rowan,
  • Cristina Naceur-Lombardelli,
  • Oliver Shutkever,
  • Carlos Martinez-Ruiz,
  • Siân Harries,
  • Sonya Hessey,
  • Babu Naidu,
  • James D. Brenton,
  • John Le Quesne,
  • Anne Thomas,
  • Cathy Richards,
  • Matthew G. Krebs,
  • Samra Turajlic,
  • Sanjay Jogai,
  • Simone Zaccaria,
  • David Moore,
  • Crispin T. Hiley,
  • John Le Quesne,
  • Kai-Keen Shiu,
  • John Bridgewater,
  • Daniel Hochhauser,
  • Martin Forster,
  • Siow Ming Lee,
  • Tanya Ahmad,
  • Dionysis Papadatos-Pastos,
  • Sam Janes,
  • Peter Van Loo,
  • Katey Enfield,
  • Ariana Huebner,
  • Sergio Quezada,
  • Stephan Beck,
  • Tariq Enver,
  • David R. Pearce,
  • Mary Falzon,
  • Ron Sinclair,
  • Zoe Rhodes,
  • Teresa Marafioti,
  • Miriam Mitchison,
  • Mark Linch,
  • Sebastian Brandner,
  • Selvaraju Veeriah,
  • Heather Shaw,
  • Gerhardt Attard,
  • Faye Gishen,
  • Maise Al-Bakir,
  • Nnenna Kanu,
  • Francisco Gimeno-Valiente,
  • Emilia L. Lim,
  • James Reading,
  • Benny Chain,
  • Adrienne Flanagan,
  • Emma Colliver,
  • Mihaela Angelova,
  • James Black,
  • Olivia Lucas,
  • William Hill,
  • Wing Kin Liu,
  • Alexander Frankell,
  • Roberto Salgado,
  • Kristiana Grigoriadis,
  • Takahiro Karasaki,
  • Abigail Bunkum,
  • Sarah Benafif,
  • Vittorio Barbè,
  • Supreet Kaur Bola,
  • Osvaldas Vainauskas,
  • Anna Wingate,
  • Daniel Wetterskog,
  • A. M. Mahedi Hasan,
  • Stefano Lise,
  • Gianmarco Leone,
  • Anuradha Jayaram,
  • Constantine Alifrangis,
  • Ursula McGovern,
  • Kerstin Thol,
  • Samuel Gamble,
  • Seng Kuong Ung,
  • Piotr Pawlik,
  • Roberto Vendramin,
  • Jayant Rane,
  • Angela Dwornik,
  • Kerry Bowles,
  • Jeanette Kittel,
  • Kerstin Haase,
  • Rija Zaidi,
  • Athanasia Vargiamiou,
  • Lucrezia Patruno,
  • Christopher Aled Chamberlain,
  • Welles Robinson,
  • Iain McNeish,
  • Nataly Ojeda Mosquera,
  • Jiali Liu,
  • Felix O’Farrell,
  • Chenelle Marcel,
  • James Larkin,
  • Lisa Pickering,
  • Andrew Furness,
  • Kate Young,
  • Will Drake,
  • Kim Edmonds,
  • Nikki Hunter,
  • Mary Mangwende,
  • Lauren Grostate,
  • Lavinia Spain,
  • Scott Shepherd,
  • Haixi Yan,
  • Benjamin Shum,
  • Zayd Tippu,
  • Brian Hanley,
  • Charlotte Spencer,
  • Max Emmerich,
  • Camille Gerard,
  • Eleanor Carlyle,
  • Steve Hazell,
  • Hardeep Mudhar,
  • Christina Messiou,
  • Arash Latifoltojar,
  • Annika Fendler,
  • Fiona Byrne,
  • Husayn Pallikonda,
  • Irene Lobon,
  • Alexander Coulton,
  • Anne-Laure Cattin,
  • Daqi Deng,
  • Hugang Feng,
  • Nadia Yousaf,
  • Sanjay Popat,
  • Charlotte Milner-Watts,
  • Emma Nye,
  • Aida Murra,
  • Justine Korteweg,
  • Lauren Terry,
  • Jennifer Biano,
  • Kema Peat,
  • Emma Turay,
  • Peter Hill,
  • Marija Miletic,
  • Anadil Javaid,
  • Jennifer Thomas,
  • Bakir Kudic,
  • Orla McGowan,
  • Dharmista Ramesh,
  • Oznur Saka,
  • Sinem Arslan,
  • Laura Marandino,
  • Reina Ammar,
  • Gurneet Kapur,
  • Dilruba Kabir,
  • David McMahon,
  • Alexius John,
  • Foteini Kalofonou,
  • Debra Josephs,
  • Sheeba Irshad,
  • James Spicer,
  • Anna Green,
  • Ruby Stewart,
  • Natasha Wright,
  • Ruxandra Mitu,
  • Deborah Enting,
  • Sarah Rudman,
  • Sharmistha Ghosh,
  • Eleni Karapanagiotou,
  • Elias Pintus,
  • Andrew Tutt,
  • Nicola Thompson,
  • Rebecca Fitzgerald,
  • Merche Jimenez-Linan,
  • Elena Provenzano,
  • Anna Paterson,
  • Kieren Allinson,
  • Grant D. Stewart,
  • Ultan McDermott,
  • Tim Maughan,
  • Olaf Ansorge,
  • Peter Campbell,
  • Patricia Roxburgh,
  • Sioban Fraser,
  • Kevin Blyth,
  • Fiona Blackhall,
  • Yvonne Summers,
  • Pedro Oliveira,
  • Caroline Dive,
  • Fabio Gomes,
  • Mat Carter,
  • Dean Fennell,
  • Jacqui Shaw,
  • Claire Wilson,
  • Charlotte Poile,
  • Kudazyi H. Kutywayo,
  • Maurice R. Dungey,
  • Jens Claus Hahne,
  • Shobhit Baijal,
  • Gerald Langman,
  • Charlotte Ferris,
  • Hollie Bancroft,
  • Amy Kerr,
  • Gary Middleton,
  • Joanne Webb,
  • Salma Kadiri,
  • Bernard Olisemeke,
  • Rodelaine Wilson,
  • Aya Osman,
  • Ian Tomlinson,
  • Judith Cave,
  • Luke Nolan,
  • Samantha Holden,
  • Tania Fernandes,
  • Dave Chuter,
  • Mairead McKenzie,
  • Allan Hackshaw,
  • Aoife Walker,
  • Hayley Bridger,
  • Rachel Leslie,
  • Shivani Patel,
  • Charles Swanton,
  • Mariam Jamal-Hanjani,
  • Nicholas McGranahan

摘要

The extent to which exogenous sources, including cancer treatment, contribute to somatic evolution in normal tissue remains unclear. Here we used high-depth duplex sequencing1 (more than 30,000× coverage) to analyse 168 cancer-free samples representing 16 organs from 22 patients with metastatic cancer enroled in the PEACE research autopsy study. In every sample, we identified somatic mutations (range 305–2,854 mutations) at low variant allele frequencies (median 0.0000323). We extracted 16 distinct single-base substitution mutational signatures, reflecting processes that have moulded the genomes of normal cells. We identified alcohol-induced mutation acquisition in liver, smoking-induced mutagenesis in lung and cardiac tissue, and multiple treatment-induced processes, which correlated with therapy type and duration. Exogenous sources, including treatment, underpinned, on average, more than 40% of mutations in liver but less than 10% of mutations in brain samples. Finally, we observed tissue-specific selection, with positive selection in tissues such as lung (PTEN and PIK3CA), liver (NF2L2) and spleen (BRAF and NOTCH2), and limited selection in others, such as brain and cardiac tissue. More than 25% of driver mutations in normal tissue exposed to systemic anti-cancer therapy, including in TP53, could be attributed to treatment. Immunotherapy, although not associated with increased mutagenesis, was linked to driver mutations in PPM1D and TP53, illustrating how non-mutagenic treatment can sculpt somatic evolution. Our study reveals the rich tapestry of mutational processes and driver mutations in normal tissue, and the profound effect of lifetime exposures, including cancer treatment, on somatic evolution.