title: Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.
abstract: Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK.
authors.forename: Elza C
authors.initials: EC
authors.lastname: de Bruin
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK. Centre for Mathematics and Physics in the Life Science and Experimental Biology (CoMPLEX), University College London, London WC1E 6BT, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: McGranahan
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Mitter
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Max
authors.initials: M
authors.lastname: Salm
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. University of Cambridge, Cambridge CB2 1TN, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Yates
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK.
authors.forename: Mariam
authors.initials: M
authors.lastname: Jamal-Hanjani
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK.
authors.forename: Seema
authors.initials: S
authors.lastname: Shafi
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK.
authors.forename: Nirupa
authors.initials: N
authors.lastname: Murugaesu
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rowan
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Grönroos
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK.
authors.forename: Madiha A
authors.initials: MA
authors.lastname: Muhammad
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Horswell
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Gerlinger
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Varela
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Voet
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.affiliation: Papworth Hospital NHS Foundation Trust, Cambridge CB23 3RE, UK.
authors.forename: Doris M
authors.initials: DM
authors.lastname: Rassl
authors.affiliation: Papworth Hospital NHS Foundation Trust, Cambridge CB23 3RE, UK.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rintoul
authors.affiliation: Lungs for Living Research Centre, University College London, London WC1E 6BT, UK.
authors.forename: Sam M
authors.initials: SM
authors.lastname: Janes
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. University College London Hospitals, London NW1 2BU, UK.
authors.forename: Siow-Ming
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. University College London Hospitals, London NW1 2BU, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Forster
authors.affiliation: University College London Hospitals, London NW1 2BU, UK.
authors.forename: Tanya
authors.initials: T
authors.lastname: Ahmad
authors.affiliation: University College London Hospitals, London NW1 2BU, UK.
authors.forename: David
authors.initials: D
authors.lastname: Lawrence
authors.affiliation: University College London Hospitals, London NW1 2BU, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Falzon
authors.affiliation: University College London Hospitals, London NW1 2BU, UK.
authors.forename: Arrigo
authors.initials: A
authors.lastname: Capitanio
authors.affiliation: Thermo Fisher Scientific, Carlsbad, CA 92008, USA.
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Harkins
authors.affiliation: Thermo Fisher Scientific, Carlsbad, CA 92008, USA.
authors.forename: Clarence C
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Thermo Fisher Scientific, Carlsbad, CA 92008, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Tom
authors.affiliation: Thermo Fisher Scientific, Carlsbad, CA 92008, USA.
authors.forename: Enock
authors.initials: E
authors.lastname: Teefe
authors.affiliation: Thermo Fisher Scientific, Carlsbad, CA 92008, USA.
authors.forename: Shann-Ching
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Sharmin
authors.initials: S
authors.lastname: Begum
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Rabinowitz
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Phillimore
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.affiliation: Technical University of Denmark, 2800 Kongens Lyngby, Denmark. Children's Hospital Informatics Program, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Nik
authors.initials: N
authors.lastname: Matthews
authors.affiliation: Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Aengus
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Campbell
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. Cancer Research UK London Research Institute, London WC2A 3LY, UK. charles.swanton@cancer.org.uk.
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D000071479:APOBEC-1 Deaminase; D002273:Carcinogens / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000175:diagnosis* / Q000235:genetics*; D003564:Cytidine Deaminase / Q000235:genetics; D019143:Evolution, Molecular; D018628:Gene Dosage; D018740:Genetic Heterogeneity; D042822:Genomic Instability; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D011379:Prognosis; D012907:Smoking / Q000009:adverse effects; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D002273:Carcinogens; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; D003564:Cytidine Deaminase