Somatic evolution following cancer treatment in normal tissue

作者：Oriol Pich, Sophia Ward, Andrew Rowan, Cristina Naceur‐Lombardelli, Oliver Shutkever, Carlos Martínez‐Ruiz, S. Harries, Sonya Hessey, Babu Naidu, James D. Brenton, John Le Quesne, Anne E. Thomas, Cathy Richards, Matthew Krebs, Samra Turajlic, Sanjay Jogai, Simone Zaccaria, David A. Moore, Crispin T. Hiley, John Le Quesne, Kai‐Keen Shiu, John Bridgewater, Daniel Hochhauser, Martin Förster, Siow Ming Lee, Tanya Ahmad, Dionysis Papadatos-Pastos, Sam M. Janes, Peter Van Loo, Katey S.S. Enfield, Ariana Huebner, Sergio A. 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 L. Reading, Benny Chain, Adrienne M. Flanagan, Emma Colliver, Mihaela Angelova, James R. Black, Olivia Lucas, William Hill, Wing Kin Liu, Alexander M. 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 Anakin Ung, Piotr Pawlik, Roberto Vendramin, Jayant K. Rane, Angela Dwornik, Kerry Bowles, Jeanette Kittel, Kerstin Haase, Rija Zaidi, Athanasia Vargiamiou, Lucrezia Patruno, Christopher A. Chamberlain, Welles Robinson, Iain A. 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 L. Gérard, Eleanor Carlyle, Steve Hazell, Hardeep Singh Mudhar, Christina Messiou, Arash Latifoltojar, Annika Fendler, Fiona Byrne, Husayn Ahmed Pallikonda, Irene Lobón, 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 Miletić, Anadil Javaid, Jennifer Thomas, Bakir Kudić, Orla McGowan, Dharmista Ramesh, Oznur Saka, Sinem Arslan, Laura Marandino, Reina Ammar, Gurneet Kapur, D. J. EL KABIR, David McMahon, Alexius John, Foteini Kalofonou, Debra H. Josephs, Sheeba Irshad, James Spicer, Anna Green, Ruby M. Stewart, Natasha Wright, Ruxandra Mitu, Deborah Enting, S. Rudman, Sharmistha Ghosh, Eleni Karapanagiotou, Elias Pintus, Andrew Tutt, Nicola Thompson, Rebecca C. Fitzgerald, Merche Jimenez-Linan, Elena Provenzano, Anna Paterson, Kieren Allinson, Grant D. Stewart, Ultan McDermott, Tim Maughan, Olaf Ansorge, Peter J. Campbell, Patricia Roxburgh, Sioban Fraser, Kevin Blyth, Fiona Blackhall, Yvonne Summers, Pedro Oliveira, Caroline Dive, Fabio M. Gomes, Mat Carter, Dean Fennell, Jacqui Shaw, Claire Wilson, Charlotte Poile, Kudazyi H. Kutywayo, Maurice 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 K. Holden, Tânia Rita Moreno de Oliveira Fernandes, Dave Chuter, Mairead McKenzie, Allan Hackshaw, Aoife Walker, Hayley Bridger, Rachel Leslie, Shivani Patel, Charles Swanton, Mariam Jamal‐Hanjani, Nicholas McGranahan · 发表于：Nature · 年份：2025 · DOI：10.1038/s41586-025-09792-4 · 被引用次数：7 · 研究领域：Cancer Genomics and Diagnostics、Evolution and Genetic Dynamics、Mathematical Biology Tumor Growth

(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 expo...