Somatic evolution following cancer treatment in normal tissue
Abstract
Abstract 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 1 (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.
Article Details
Authors (218)
Oriol Pich
Sophia Ward
Andrew Rowan
Cristina Naceur-Lombardelli
Oliver Shutkever
Carlos Martínez-Ruiz
Sian Harries
Sonya Hessey
Babu Naidu
James D. Brenton
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