Somatic evolution following cancer treatment in normal tissue
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
Abstract
(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.