Mariam Jamal-Hanjani1, Gareth A Wilson1, Nicholas McGranahan1, Nicolai J Birkbak1, Thomas B K Watkins1, Selvaraju Veeriah1, Seema Shafi1, Diana H Johnson1, Richard Mitter1, Rachel Rosenthal1, Max Salm1, Stuart Horswell1, Mickael Escudero1, Nik Matthews1, Andrew Rowan1, Tim Chambers1, David A Moore1, Samra Turajlic1, Hang Xu1, Siow-Ming Lee1, Martin D Forster1, Tanya Ahmad1, Crispin T Hiley1, Christopher Abbosh1, Mary Falzon1, Elaine Borg1, Teresa Marafioti1, David Lawrence1, Martin Hayward1, Shyam Kolvekar1, Nikolaos Panagiotopoulos1, Sam M Janes1, Ricky Thakrar1, Asia Ahmed1, Fiona Blackhall1, Yvonne Summers1, Rajesh Shah1, Leena Joseph1, Anne M Quinn1, Phil A Crosbie1, Babu Naidu1, Gary Middleton1, Gerald Langman1, Simon Trotter1, Marianne Nicolson1, Hardy Remmen1, Keith Kerr1, Mahendran Chetty1, Lesley Gomersall1, Dean A Fennell1, Apostolos Nakas1, Sridhar Rathinam1, Girija Anand1, Sajid Khan1, Peter Russell1, Veni Ezhil1, Babikir Ismail1, Melanie Irvin-Sellers1, Vineet Prakash1, Jason F Lester1, Malgorzata Kornaszewska1, Richard Attanoos1, Haydn Adams1, Helen Davies1, Stefan Dentro1, Philippe Taniere1, Brendan O'Sullivan1, Helen L Lowe1, John A Hartley1, Natasha Iles1, Harriet Bell1, Yenting Ngai1, Jacqui A Shaw1, Javier Herrero1, Zoltan Szallasi1, Roland F Schwarz1, Aengus Stewart1, Sergio A Quezada1, John Le Quesne1, Peter Van Loo1, Caroline Dive1, Allan Hackshaw1, Charles Swanton1. 1. From the Cancer Research UK Lung Cancer Centre of Excellence (M.J.-H., G.A.W., N. McGranahan, N.J.B., S.V., S.S., D.H.J., R.R., S.-M.L., M.D.F., C.A., S.M.J., C.D., C.S.), London and Manchester, Good Clinical Laboratory Practice Facility, University College London (UCL) Experimental Cancer Medicine Centre (H.L.L., J.A.H.), Bill Lyons Informatics Centre (J.H.), and Cancer Immunology Unit (S.A.Q.), UCL Cancer Institute, the Translational Cancer Therapeutics Laboratory (G.A.W., N. McGranahan, N.J.B., T.B.K.W., A.R., T.C., S. Turajlic, H.X., C.T.H., C.S.), Department of Bioinformatics and Biostatistics (R.M., M.S., S.H., M.E., A.S.), Advanced Sequencing Facility (N. Matthews), and Cancer Genomics Laboratory (S.D., P.V.L.), Francis Crick Institute, the Renal and Skin Units, Royal Marsden Hospital (S. Turajlic), the Departments of Medical Oncology (M.J.-H., S.-M.L., M.D.F., T.A., C.A., C.S.), Pathology (M.F., E.B., T.M.), Cardiothoracic Surgery (D.L., M.H., S. Kolvekar, N.P.), Respiratory Medicine (S.M.J., R.T.), and Radiology (A.A.), UCL Hospitals, Lungs for Living, UCL Respiratory, UCL (S.M.J.), the Department of Radiotherapy, North Middlesex University Hospital (G.A.), the Department of Respiratory Medicine, Royal Free Hospital (S. Khan), and UCL Cancer Research UK and Cancer Trials Centre (N.I., H.B., Y.N., A.H.), London, Cancer Studies, University of Leicester (D.A.M., D.A.F., J.A.S., J.L.Q.), the Department of Thoracic Surgery, Glenfield Hospital (A.N., S.R.), and the Medical Research Center Toxicology Unit (J.L.Q.), Leicester, the Institute of Cancer Studies, University of Manchester (F.B.), the Christie Hospital (F.B., Y.S.), the Departments of Cardiothoracic Surgery (R.S.) and Pathology (L.J., A.M.Q.) and the North West Lung Centre (P.A.C.), University Hospital of South Manchester, and Cancer Research UK Manchester Institute (C.D.), Manchester, the Departments of Thoracic Surgery (B.N.) and Cellular Pathology (G.L., S. Trotter), Birmingham Heartlands Hospital, Molecular Pathology Diagnostic Services, Queen Elizabeth Hospital (P.T., B.O.), and Institute of Immunology and Immunotherapy, University of Birmingham (G.M.), Birmingham, the Departments of Medical Oncology (M.N.), Cardiothoracic Surgery (H.R.), Pathology (K.K.), Respiratory Medicine (M.C.), and Radiology (L.G.), Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen, the Department of Respiratory Medicine, Barnet and Chase Farm Hospitals, Barnet (S. Khan), the Department of Respiratory Medicine, Princess Alexandra Hospital, Harlow (P.R.), the Department of Clinical Oncology, St. Luke's Cancer Centre, Guildford (V.E.), the Departments of Pathology (B.I.), Respiratory Medicine (M.I.-S.), and Radiology (V.P.), Ashford and St. Peters' Hospitals, Surrey, the Department of Clinical Oncology, Velindre Hospital (J.F.L.), the Departments of Radiology (H.A.) and Respiratory Medicine (H.D.), University Hospital Llandough, the Departments of Pathology (R.A.) and Cardiothoracic Surgery (M.K.), University Hospital of Wales, and Cardiff University (R.A.), Cardiff, and Wellcome Trust Sanger Institute, Hinxton, and Big Data Institute, University of Oxford, Oxford (S.D.) - all in the United Kingdom; the Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby (Z.S.); the Computational Health Informatics Program, Boston Children's Hospital and Harvard Medical School, Boston (Z.S.); MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary (Z.S.); Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin (R.F.S.); and the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.).
Abstract
BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis. CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).
BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis. CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).
Authors: Hongping Zheng; Yotsawat Pomyen; Maria Olga Hernandez; Caiyi Li; Ferenc Livak; Wei Tang; Hien Dang; Tim F Greten; Jeremy L Davis; Yongmei Zhao; Monika Mehta; Yelena Levin; Jyoti Shetty; Bao Tran; Anuradha Budhu; Xin Wei Wang Journal: Hepatology Date: 2018-05-09 Impact factor: 17.425
Authors: Lucas W Thornblade; Michael S Mulligan; Katherine Odem-Davis; Billanna Hwang; Rachel L Waworuntu; Erika M Wolff; Larry Kessler; Douglas E Wood; Farhood Farjah Journal: Ann Thorac Surg Date: 2018-07-19 Impact factor: 4.330
Authors: Winifred Lo; Maria Parkhurst; Paul F Robbins; Eric Tran; Yong-Chen Lu; Li Jia; Jared J Gartner; Anna Pasetto; Drew Deniger; Parisa Malekzadeh; Thomas E Shelton; Todd Prickett; Satyajit Ray; Scott Kivitz; Biman C Paria; Isaac Kriley; David S Schrump; Steven A Rosenberg Journal: Cancer Immunol Res Date: 2019-02-01 Impact factor: 11.151