跟踪非小细胞肺癌的演变。

Tracking the Evolution of Non-Small-Cell Lung Cancer.

机构信息

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.).

出版信息

N Engl J Med. 2017 Jun 1;376(22):2109-2121. doi: 10.1056/NEJMoa1616288. Epub 2017 Apr 26.

DOI:10.1056/NEJMoa1616288

PMID:28445112

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), 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 .).

摘要

背景

在非小细胞肺癌（NSCLC）患者中，关于肿瘤内异质性和癌症基因组进化的数据仅限于小型回顾性队列。我们希望前瞻性地研究肿瘤内异质性与临床结局的关系，并确定早期 NSCLC 中驱动事件和进化过程的克隆性质。

方法

在这项前瞻性队列研究中，我们对 100 例在系统治疗前切除的早期 NSCLC 肿瘤进行了多区域全外显子组测序。我们对 327 个肿瘤区域进行测序和分析，以定义进化史，获得克隆和亚克隆事件的普查，并评估肿瘤内异质性与无复发生存之间的关系。

结果

我们观察到体细胞拷贝数改变和突变的广泛肿瘤内异质性。EGFR、MET、BRAF 和 TP53 中的驱动突变几乎总是克隆的。然而，在进化后期发生的异质性驱动改变在超过 75%的肿瘤中发现，在 PIK3CA 和 NF1 以及参与染色质修饰和 DNA 损伤反应和修复的基因中很常见。基因组加倍和持续的动态染色体不稳定性与肿瘤内异质性相关，并导致驱动体细胞拷贝数改变的平行进化，包括 CDK4、FOXA1 和 BCL11A 的扩增。拷贝数异质性升高与复发或死亡的风险增加相关（风险比，4.9；P=4.4×10），在多变量分析中仍然具有统计学意义。