Evolutionary characterization of lung cancer metastasis
Abstract
Abstract Limited understanding of the biological processes that govern metastatic dissemination hinders its prevention and treatment 1 . Here, using 501 longitudinally collected primary and metastatic tumour samples from 24 patients with non-small cell lung cancer (NSCLC) enrolled in the TRACERx lung study and PEACE autopsy programme, we infer tumour evolution from diagnosis to death. With DNA-sequencing data encompassing 70% of the metastases that were radiologically detected before death and paired multi-region sampled primary tumours, we show that the genomes of metastases diverge markedly from those of their ancestral primary tumour, with additional driver alterations and genome doubling events occurring after metastatic dissemination. In 62.5% of patients, multiple primary tumour subclones disseminated, each founding a distinct metastasis. These metastases served as sources of onward spread: more than half of the metastases sampled were seeded by other metastases. The duration that metastases existed in situ influenced their likelihood of seeding further metastases. Most metastatic migrations started and ended in the same anatomical cavity. The few subclones that exited the thorax to seed metastases disseminated widely and were enriched for somatic copy-number alterations, suggesting that chromosomal instability may facilitate extrathoracic spread. This spatial and temporal evolutionary analysis sheds light on the extent of metastatic diversity and seeding in advanced NSCLC—which tends to be underestimated in single metastasis biopsies—and identifies genomic and clinical mediators of metastatic progression.
Article Details
Authors (438)
Sonya Hessey
Abigail Bunkum
Ariana Huebner
Kerstin Haase
Kristiana Grigoriadis
Cristina Naceur-Lombardelli
Wing Kin Liu
Caitlin F. Harrigan
Charlotte Grieco
Daniele Marinelli
Boyue Ding
Carlos Martínez-Ruiz
Piotr Pawlik
Mark S. Hill
Olivia Lucas
Corentin Richard
Oriol Pich
Kerstin Thol
Takahiro Karasaki
Sophia Ward
Foteini Athanasopoulou
Monica Sivakumar
Selvaraju Veeriah
Antonia Toncheva
Andrew J. Rowan
Paulina Prymas
Hayley Bridger
Miriam Mitchison
Elaine Borg
Mary Falzon
Ian Proctor
Ula Mahadeva
Anna Green
Martin D. Forster
Sarah Benafif
Tanya Ahmad
Siow Ming Lee
Dionysis Papadatos-Pastos
Babu Naidu
Gerald Langman
Matthew G. Krebs
Pedro Oliveira
Fiona H. Blackhall
Yvonne Summers
Jamie Weaver
Anne Thomas
Cathy Richards
Dean A. Fennell
Sanjay Jogai
Judith Cave
Patricia Roxburgh
Sioban Fraser
Alan Kirk
Kevin G. Blyth
Peter Russell
Crispin T. Hiley
Allan Hackshaw
John Le Quesne
Jason F. Lester
Amrita Bajaj
Apostolos Nakas
Azmina Sodha-Ramdeen
Claire Wilson
Molly Scotland
Rebecca Boyles
Sean Dulloo
Sridhar Rathinam
Gurdeep Matharu
Jacqui A. Shaw
Ekaterini Boleti
Heather Cheyne
Gillian Price
Keith M. Kerr
Mohammed Khalil
Shirley Richardson
Tracey Cruickshank
Jack French
Kayleigh Gilbert
Akshay J. Patel
Aya Osman
Gary Middleton
Helen Shackleford
Madava Djearaman
Mandeesh Sangha
Angela Leek
Adam Atkin
Anshuman Chaturvedi
Antonio Paiva-Correia
Colin R. Lindsay
Eustace Fontaine
Felice Granato
Jack Davies Hodgkinson
Juliette Novasio
Katherine D. Brown
Kandadai Rammohan
Leena Joseph
Mathew Carter
Nicola Totton
Paul Bishop
Philip A. J. Crosbie
Sara Waplington
Jonathan Tugwood
Caroline Dive
Hugo JWL Aerts
Gareth A. Wilson
Aino-Maija Leppä
Alexander A. Azizi
Lydia Y. Liu
Jonas Demeulemeester
Miklos Diossy
Nicolai J. Birkbak
Peter Van Loo
Rachel Rosenthal
Roberto Salgado
Roland F. Schwarz
Tom L. Kaufmann
Zoltan Szallasi
Alexander M. Frankell
Angela Dwornik
Angeliki Karamani
Karen Grimes
Benny Chain
Carla Castignani
Chris Bailey
Cian Murphy
Clare E. Weeden
Clare Puttick
David R. Pearce
Despoina Karagianni
Dimitria Brempou
Emilia L. Lim
Emma C. Colliver
Emma Hazelwood
Emma Nye
Erik Sahai
Eva Grönroos
Francisco Gimeno-Valiente
Gemma Foulds
George Kassiotis
Georgia Moth
Georgia Stavrou
Helen L. Lowe
Ieva Usaite
Iva Mladenova
Jacki Goldman
James L. Reading
James R. M. Black
Jayant K. Rane
Jeanette Kittel
John A. Hartley
Jorge Martin Arana
Karl S. Peggs
Katey S. S. Enfield
Katherine Honan
Kayalvizhi Selvaraju
Kexin Koh
Krupa Thakkar
Leah Ensell
Lucrezia Patruno
Maise Al Bakir
Mansi Shah
Maria Litovchenko
Maria Zagorulya
Michalina Magala
Michelle M. Leung
Mickael Escudero
Mihaela Angelova
Oliver Shutkever
Philip Hobson
Richard Kevin Stone
Rija Zaidi
Robert Bentham
Robert Goldstone
Roberto Vendramin
Sadegh Saghafinia
Samuel Gamble
Seng Kuong Anakin Ung
Sergio A. Quezada
Sharon Vanloo
Sian Harries
Stefan Boeing
Stephan Beck
Supreet Kaur Bola
Teresa Marafioti
Theepan Visakan
Thomas B. K. Watkins
Thomas Patrick Jones
Victoria Spanswick
Vittorio Barbè
Wei-Ting Lu
William Hill
Woody Z. Zhang
Yin Wu
Yutaka Naito
Zoe Ramsden
Catarina Veiga
Charles-Antoine Collins-Fekete
Francesco Fraioli
Gary Royle
Paul Ashford
Alexander James Procter
Arjun Nair
Asia Ahmed
David Lawrence
Davide Patrini
Emilie Martinoni Hoogenboom
Fleur Monk
James W. Holding
Junaid Choudhary
Kunal Bhakhri
Magali N. Taylor
Maria Chiara Pisciella
Neal Navani
Pat Gorman
Reena Khiroya
Ricky M. Thakrar
Robert CM Stephens
Sam M. Janes
Steve Bandula
Zoltan Kaplar
Aoife Walker
Camilla Pilotti
Rachel Leslie
Salomey Kellett
Anca Grapa
Hanyun Zhang
Khalid AbdulJabbar
Xiaoxi Pan
Yinyin Yuan
David Chuter
Mairead MacKenzie
Aiman Alzetani
Patricia Georg
Serena Chee
Eric Lim
Alexandra Rice
Anand Devaraj
Andrew G. Nicholson
Chiara Proli
Daniel Kaniu
Harshil Bhayani
Hema Chavan
Hilgardt Raubenheimer
Lyn Ambrose
Mpho Malima
Nadia Fernandes
Paulo De Sousa
Pratibha Shah
Sarah Booth
Silviu I. Buderi
Simon Jordan
Sofina Begum
Madeleine Hewish
Sarah Danson
Michael J. Shackcloth
Lily Robinson
Andrew Kidd
Craig Dick
Jennifer Whiteley
Mathew Thomas
Mohammed Asif
Nikos Kostoulas
Rocco Bilancia
Zainab Kalokoh
Elizabeth Keene
Theepan Vikasan
Karen Ambrose
Mike Gavrielides
Nitzan Rosenfeld
Amrit Roshan
Cecilie Agergaard Soerensen
Ben Solomon
Lavinia Tan
Ana Parreira
Corinne Faivre-Finn
Fabio Gomes
Igor Gomez-Randulfe
Jack Webster
Laura Cove-Smith
Pamela Maroa
Paul Taylor
Raffaele Califano
Sara Tenconi
Adam Peryt
Aman Coonar
Amanda Stone
Caroline Sanganee
Martin Goddard
Stephen Preston
Giuseppe Aresu
Jane Lichfield
Julia Knight
Lauren DSA
Maria Manuela Urda
Maria Nizami
Robert Rintoul
Zoe Armstrong
Abiya Mathew
Damalie Namwanja
Nicky Thomson
Philip Earwaker
Kai-Keen Shiu
John Bridgewater
Daniel Hochhauser
Tariq Enver
Ron Sinclair
Zoe Rhodes
Mark Linch
Sebastian Brandner
Heather Shaw
Gerhardt Attard
Faye Gishen
Nnennaya Kanu
Francisco Gimeno Valiente
Adrienne Flanagan
Osvaldas Vainauskas
Anna Wingate
Daniel Wetterskog
A. M. Mahedi Hasan
Stefano Lise
Gianmarco Leone
Anuradha Jayaram
Constantine Alifrangis
Ursula McGovern
Kerry Bowles
Athanasia Vargiamiou
Christopher Aled Chamberlain
Welles Robinson
Iain McNeish
Nataly Ojeda Mosquera
Jiali Liu
Felix O’Farrell
Chenelle Marcel
Samra Turajlic
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
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
Ruby Stewart
Natasha Wright
Ruxandra Mitu
Deborah Enting
Sarah Rudman
Sharmistha Ghosh
Eleni Lena Karapanagiotou
Elias Pintus
Andrew Tutt
James D. Brenton
Nicola Thompson
Rebecca Fitzgerald
Merche Jimenez-Linan
Elena Provenzano
Anna Paterson
Kieren Allinson
Grant D. Stewart
Ultan McDermott
Tim Maughan
Olaf Ansorge
Peter Campbell
Mat Carter
Charlotte Poile
Kudazyi H. Kutywayo
Maurice R. Dungey
Jens Claus Hahne
Shobhit Baijal
Charlotte Ferris
Hollie Bancroft
Amy Kerr
Joanne Webb
Salma Kadiri
Bernard Olisemeke
Rodelaine Wilson
Ian Tomlinson
Luke Nolan
Samantha Holden
Tania Fernandes
Mairead McKenzie
Shivani Patel
David A. Moore
Simone Zaccaria
Nicholas McGranahan
Charles Swanton
Mariam Jamal-Hanjani