提示: 手机请竖屏浏览!

追踪非小细胞肺癌的进化
Tracking the Evolution of Non-Small-Cell Lung Cancer


Mariam Jamal-Hanjani ... 肿瘤 呼吸系统疾病 • 2017.06.01
相关阅读
• 使用奥希替尼治疗未经治疗的EGFR突变晚期NSCLC • 染色体不稳定性可能是非小细胞肺癌的预后相关因素 • 透过系统发生树了解癌症进化“森林”

追踪非小细胞肺癌“进化”的临床意义

 

张绪超

广东省人民医院;广东省肺癌研究所

 

在1858年,英国伦敦林奈学会发表了达尔文和华莱士关于“物种变异与自然选择”的论文,开启了进化论的研究思潮,最终确立了“进化”在物种起源与演化过程中的重大意义。

查看更多

摘要


背景

迄今,非小细胞肺癌(NSCLC)患者瘤内异质性和癌症基因组进化数据的获取仅限于小规模的回顾性队列。我们的目的是前瞻性探索瘤内异质性与临床结局之间的关联,以及确定早期NSCLC驱动事件的克隆性和进化过程。

 

方法

在这项前瞻性队列研究中,我们对全身性治疗开始前切除的100个早期NSCLC肿瘤进行了多区域的全外显子组测序。我们测序并分析了327个肿瘤区域,以定义肿瘤进化史,获得克隆和亚克隆事件的统计数字,并评估瘤内异质性和无再发生存之间的关联。

 

结果

我们观察到广泛存在的瘤内异质性,体现为体细胞基因拷贝数变异和突变。EGFRMETBRAFTP53的驱动突变几乎总是克隆性的,但是在肿瘤进化的后期,超过75%的肿瘤内存在异质的驱动变异,并且这些突变普遍发生在PIK3CANF1,以及参与染色质修饰、DNA损伤应答和修复的基因内。基因组加倍和染色体的持续动态不稳定与瘤内异质性相关,导致驱动性体细胞基因拷贝数变异发生平行进化,其中包括CDK4FOXA1BCL11A的扩增。拷贝数异质性的加剧与再发或死亡风险的增加相关(风险比,4.9;P=4.4×10-4),这种相关性在多变量统计分析中仍然显著。

 

结论

通过染色体不稳定性介导的肿瘤异质性与再发和死亡风险的增加相关。这一发现支持染色体不稳定性作为预后预测指标的潜在价值(该研究由英国癌症研究学会[Cancer Research UK]等资助;TRACERx在ClinicalTrials.gov注册号为NCI01888601)。





作者信息

Mariam Jamal-Hanjani, M.D., Ph.D., Gareth A. Wilson, Ph.D., Nicholas McGranahan, Ph.D., Nicolai J. Birkbak, Ph.D., Thomas B.K. Watkins, M.C.I.T., Selvaraju Veeriah, Ph.D., Seema Shafi, Ph.D., Diana H. Johnson, B.Sc., Richard Mitter, M.Sc., Rachel Rosenthal, M.Sc., Max Salm, Ph.D., Stuart Horswell, M.Math., Mickael Escudero, M.Sc., Nik Matthews, B.Sc., Andrew Rowan, B.Sc., Tim Chambers, M.Sc., David A. Moore, M.D., Samra Turajlic, M.D., Ph.D., Hang Xu, Ph.D., Siow-Ming Lee, M.D., Ph.D., Martin D. Forster, M.D., Ph.D., Tanya Ahmad, M.D., Crispin T. Hiley, M.D., Ph.D., Christopher Abbosh, M.D., Mary Falzon, M.D., Elaine Borg, M.D., Teresa Marafioti, M.D., David Lawrence, M.D., Martin Hayward, M.D., Shyam Kolvekar, M.D., Nikolaos Panagiotopoulos, M.D., Sam M. Janes, M.D., Ph.D., Ricky Thakrar, M.D., Asia Ahmed, M.D., Fiona Blackhall, M.D., Ph.D., Yvonne Summers, M.D., Ph.D., Rajesh Shah, M.D., Leena Joseph, M.D., Anne M. Quinn, M.D., Ph.D., Phil A. Crosbie, M.D., Ph.D., Babu Naidu, M.D., Gary Middleton, M.D., Gerald Langman, M.D., Simon Trotter, M.D., Marianne Nicolson, M.D., Hardy Remmen, M.D., Keith Kerr, M.D., Mahendran Chetty, M.D., Lesley Gomersall, M.D., Dean A. Fennell, M.D., Ph.D., Apostolos Nakas, M.D., Sridhar Rathinam, M.D., Girija Anand, M.D., Sajid Khan, M.D., Peter Russell, M.D., Ph.D., Veni Ezhil, M.D., Babikir Ismail, M.D., Melanie Irvin-Sellers, M.D., Vineet Prakash, M.D., Jason F. Lester, M.D., Malgorzata Kornaszewska, M.D., Ph.D., Richard Attanoos, M.D., Haydn Adams, M.D., Helen Davies, M.D., Stefan Dentro, M.Sc., Philippe Taniere, M.D., Ph.D., Brendan O’Sullivan, B.Sc., Helen L. Lowe, Ph.D., John A. Hartley, Ph.D., Natasha Iles, Ph.D., Harriet Bell, M.Sc., Yenting Ngai, B.Sc., Jacqui A. Shaw, Ph.D., Javier Herrero, Ph.D., Zoltan Szallasi, M.D., Roland F. Schwarz, Ph.D., Aengus Stewart, M.Sc., Sergio A. Quezada, Ph.D., John Le Quesne, M.D., Ph.D., Peter Van Loo, Ph.D., Caroline Dive, Ph.D., Allan Hackshaw, M.Sc., and Charles Swanton, M.D., Ph.D., for the TRACERx Consortium*
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.). Address reprint requests to Dr. Swanton at the Translational Cancer Therapeutics Laboratory, Francis Crick Institute, 3rd Fl. SW, 1 Midland Rd., London NW1 1AT, United Kingdom, or at charles.swanton@crick.ac.uk.A complete list of investigators in the Tracking Non–Small-Cell Lung Cancer Evolution through Therapy (TRACERx) Consortium is provided in Supplementary Appendix 1, available at NEJM.org.

 

参考文献

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30

2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90

3. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-550

4. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-525

5. Imielinski M, Berger AH, Hammerman PS, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012;150:1107-1120

6. Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012;150:1121-1134

7. Campbell JD, Alexandrov A, Kim J, et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet 2016;48:607-616

8. de Bruin EC, McGranahan N, Mitter R, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 2014;346:251-256

9. Zhang J, Fujimoto J, Zhang J, et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 2014;346:256-259

10. Jamal-Hanjani M, Hackshaw A, Ngai Y, et al. Tracking genomic cancer evolution for precision medicine: the lung TRACERx study. PLoS Biol 2014;12:e1001906-e1001906

11. Alexandrov LB, Nik-Zainal S, Siu HC, Leung SY, Stratton MR. A mutational signature in gastric cancer suggests therapeutic strategies. Nat Commun 2015;6:8683-8683

12. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature 2013;500:415-421

13. Alexandrov LB, Jones PH, Wedge DC, et al. Clock-like mutational processes in human somatic cells. Nat Genet 2015;47:1402-1407

14. Roberts SA, Lawrence MS, Klimczak LJ, et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet 2013;45:970-976

15. Carter SL, Cibulskis K, Helman E, et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol 2012;30:413-421

16. Dewhurst SM, McGranahan N, Burrell RA, et al. Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discov 2014;4:175-185

17. Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 2005;437:1043-1047

18. Martincorena I, Roshan A, Gerstung M, et al. Tumor evolution: high burden and pervasive positive selection of somatic mutations in normal human skin. Science 2015;348:880-886

19. Lohr JG, Stojanov P, Carter SL, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 2014;25:91-101

20. Lawrence MS, Stojanov P, Mermel CH, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014;505:495-501

21. Middleton G, Crack LR, Popat S, et al. The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer. Ann Oncol 2015;26:2464-2469

22. Abrams J, Conley B, Mooney M, et al. National Cancer Institute’s Precision Medicine Initiatives for the new National Clinical Trials Network. Am Soc Clin Oncol Educ Book2014;:71-76

23. Greaves M. Evolutionary determinants of cancer. Cancer Discov 2015;5:806-820

24. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-2516

25. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-957

26. Cao Y, Xiao G, Qiu X, Ye S, Lin T. Efficacy and safety of crizotinib among Chinese EML4-ALK-positive, advanced-stage non-small cell lung cancer patients. PLoS One 2014;9:e114008-e114008

27. McGranahan N, Burrell RA, Endesfelder D, Novelli MR, Swanton C. Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep 2012;13:528-538

28. Ni X, Zhuo M, Su Z, et al. Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients. Proc Natl Acad Sci U S A 2013;110:21083-21088

服务条款 | 隐私政策 | 联系我们