Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.
Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.
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DOI：
10.1038/s41586-023-05776-4
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发表时间：
2023-04
期刊：
影响因子：
64.8
通讯作者：
Swanton C
中科院分区：
文献类型：
--
作者：
Abbosh C;Frankell AM;Harrison T;Kisistok J;Garnett A;Johnson L;Veeriah S;Moreau M;Chesh A;Chaunzwa TL;Weiss J;Schroeder MR;Ward S;Grigoriadis K;Shahpurwalla A;Litchfield K;Puttick C;Biswas D;Karasaki T;Black JRM;Martínez-Ruiz C;Bakir MA;Pich O;Watkins TBK;Lim EL;Huebner A;Moore DA;Godin-Heymann N;L'Hernault A;Bye H;Odell A;Roberts P;Gomes F;Patel AJ;Manzano E;Hiley CT;Carey N;Riley J;Cook DE;Hodgson D;Stetson D;Barrett JC;Kortlever RM;Evan GI;Hackshaw A;Daber RD;Shaw JA;Aerts HJWL;Licon A;Stahl J;Jamal-Hanjani M;TRACERx Consortium;Birkbak NJ;McGranahan N;Swanton C
循环肿瘤DNA（ctDNA）可以检测和分析治疗性治疗后持续存在的残留肿瘤细胞。需要结合纵向血浆采样和延长随访的大型患者队列来确定ctDNA作为早期非小细胞肺癌（NSCLC）复发的系统发育生物标志物的作用。在这里，我们开发了ctDNA方法，追踪从TRACERx研究中招募的197名患者中收集的1069份血浆样本中切除的NSCLC组织中鉴定的中位数为200个突变。缺乏术前ctDNA检测可区分生物学惰性肺腺癌，具有良好的临床结局。在标准治疗放射学监测和细胞毒性辅助治疗给药的背景下解释术后血浆分析。对术后120天内收集的血浆样本进行的地标分析显示，25%的患者检出ctDNA，包括49%经历临床复发的所有患者; 3至6个月的ctDNA监测在另外20%的地标阴性患者中确定了即将发生的疾病复发。我们开发了一种生物信息学工具（ECLIPSE），用于在低ctDNA水平下非侵入性跟踪亚克隆结构。ECLIPSE确定了多克隆转移性播散的患者，这与临床结局较差相关。通过测量术前血浆中的亚克隆癌细胞分数，我们发现与非转移性亚克隆相比，接种未来转移的亚克隆显著更多地扩增。我们的研究结果将支持（新）辅助试验的进展，并提供新的见解转移性传播的过程中使用低ctDNA水平的液体活检。
Circulating tumour DNA (ctDNA) can detect and profile residual tumour cells persisting after curative intent therapy. Large patient cohorts incorporating longitudinal plasma sampling and extended follow-up are required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here, we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1069 plasma samples collected from 197 patients enrolled in the TRACERx study. Lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days post-surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with poor clinical outcome. Through measuring subclone cancer cell fractions in preoperative plasma, we found subclones seeding future metastases were significantly more expanded compared to non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide new insights into the process of metastatic dissemination using low ctDNA level liquid biopsy.
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影响因子：
64.8
作者：
Frankell, Alexander M.;Dietzen, Michelle;Al Bakir, Maise;Lim, Emilia L.;Karasaki, Takahiro;Ward, Sophia;Veeriah, Selvaraju;Colliver, Emma;Huebner, Ariana;Bunkum, Abigail;Hill, Mark S.;Grigoriadis, Kristiana;Moore, David A.;Black, James R. M.;Liu, Wing Kin;Thol, Kerstin;Pich, Oriol;Watkins, Thomas B. K.;Naceur-Lombardelli, Cristina;Cook, Daniel E.;Salgado, Roberto;Wilson, Gareth A.;Bailey, Chris;Angelova, Mihaela;Bentham, Robert;Martinez-Ruiz, Carlos;Abbosh, Christopher;Nicholson, Andrew G.;Le Quesne, John;Biswas, Dhruva;Rosenthal, Rachel;Puttick, Clare;Hessey, Sonya;Lee, Claudia;Prymas, Paulina;Toncheva, Antonia;Smith, Jon;Xing, Wei;Nicod, Jerome;Price, Gillian;Kerr, Keith M.;Naidu, Babu;Middleton, Gary;Blyth, Kevin G.;Fennell, Dean A.;Forster, Martin D.;Lee, Siow Ming;Falzon, Mary;Hewish, Madeleine;Shackcloth, Michael J.;Lim, Eric;Benafif, Sarah;Russell, Peter;Boleti, Ekaterini;Krebs, Matthew G.;Lester, Jason F.;Papadatos-Pastos, Dionysis;Ahmad, Tanya;Thakrar, Ricky M.;Lawrence, David;Navani, Neal;Janes, Sam M.;Dive, Caroline;Blackhall, Fiona H.;Summers, Yvonne;Cave, Judith;Marafioti, Teresa;Herrero, Javier;Quezada, Sergio A.;Peggs, Karl S.;Schwarz, Roland F.;Van Loo, Peter;Miedema, Daniel M.;Birkbak, Nicolai J.;Hiley, Crispin T.;Hackshaw, Allan;Zaccaria, Simone;Jamal-Hanjani, Mariam;McGranahan, Nicholas;Swanton, Charles;Bajaj, Amrita;Nakas, Apostolos;Sodha-Ramdeen, Azmina;Ang, Keng;Tufail, Mohamad;Chowdhry, Mohammed Fiyaz;Scotland, Molly;Boyles, Rebecca;Rathinam, Sridhar;Wilson, Claire;Marrone, Domenic;Dulloo, Sean;Matharu, Gurdeep;Shaw, Jacqui A.;Riley, Joa;Primrose, Lindsay;Cheyne, Heather;Khalil, Mohammed;Richardson, Shirley;Cruickshank, Tracey;Gilbert, Kayleigh;Patel, Akshay J.;Osman, Aya;Lacson, Christer;Langman, Gerald;Shackleford, Helen;Djearaman, Madava;Kadiri, Salma;Leek, Angela;Hodgkinson, Jack Davies;Totten, Nicola;Montero, Angeles;Smith, Elaine;Fontaine, Eustace;Granato, Felice;Doran, Helen;Novasio, Juliette;Rammohan, Kendadai;Joseph, Leena;Bishop, Paul;Shah, Rajesh;Moss, Stuart;Joshi, Vijay;Crosbie, Philip;Gomes, Fabio;Brown, Kate;Carter, Mathew;Chaturvedi, Anshuman;Priest, Lynsey;Oliveira, Pedro;Lindsay, Colin R.;Clipson, Alexandra;Tugwood, Jonathan;Kerr, Alastair;Rothwell, Dominic G.;Kilgour, Elaine;Aerts, Hugo J. W. L.;Kaufmann, Tom L.;Szallasi, Zoltan;Kisistok, Judit;Sokac, Mateo;Diossy, Miklos;Demeulemeester, Jonas;Stewart, Aengus;Magness, Alastair;Rowan, Andrew;Karamani, Angeliki;Chain, Benny;Campbell, Brittany B.;Castignani, Carla;Weeden, Clare E.;Richard, Corentin;Pearce, David R.;Karagianni, Despoina;Levi, Dina;Hoxha, Elena;Larose Cadieux, Elizabeth;Nye, Emma;Gronroos, Eva;Galvez-Cancino, Felip;Athanasopoulou, Foteini;Gimeno-Valiente, Francisco;Kassiotis, George;Stavrou, Georgia;Mastrokalos, Gerasimos;Zhai, Haoran L.;Lowe, Helen L.;Matos, Ignacio;Goldman, Jacki;Reading, James L.;Rane, Jayant K.;Lam, Jie Min;Hartley, John A.;Enfield, Katey S. S.;Selvaraju, Kayalvizhi;Litchfield, Kevin;Ng, Kevin W.;Chen, Kezhong;Dijkstra, Krijn;Thakkar, Krupa;Ensell, Leah;Shah, Mansi;Vasquez, Marcos;Litovchenko, Maria;Werner Sunderland, Mariana;Leung, Michelle;Escudero, Mickael;Tanic, Miljana;Sivakumar, Monica;Kanu, Nnennaya;Chervova, Olga;Lucas, Olivia;Al-Sawaf, Othman;Hobson, Philip;Pawlik, Piotr;Stone, Richard Kevin;Hynds, Robert E.;Vendramin, Roberto;Saghafinia, Sadegh;Lopez, Saioa;Gamble, Samuel;Ung, Seng Kuong Anakin;Vanloo, Sharon;Boeing, Stefan;Beck, Stephan;Bola, Supreet Kaur;Denner, Tamara;Mourikis, Thanos P.;Spanswick, Victoria;Barbe, Vittorio;Lu, Wei-Ting;Hill, William;Wu, Yin;Naito, Yutaka;Ramsden, Zoe;Veiga, Catarina;Royle, Gary;Collins-Fekete, Charles-Antoine;Fraioli, Francesco;Ashford, Paul;Clark, Tristan;Borg, Elaine;Wilson, James;Procter, Alexander James;Ahmed, Asia;Taylor, Magali N.;Nair, Arjun;Patrini, Davide;Martinoni Hoogenboom, Emilie;Monk, Fleur;Holding, James W.;Choudhary, Junaid;Bhakhri, Kunal;Scarci, Marco;Hayward, Martin;Panagiotopoulos, Nikolaos;Gorman, Pat;Khiroya, Reena;Stephens, Robert C. M.;Wong, Yien Ning Sophia;Bandula, Steve;Sharp, Abigail;Smith, Sean;Gower, Nicole;Dhanda, Harjot Kaur;Chan, Kitty;Pilotti, Camilla;Leslie, Rachel;Grapa, Anca;Zhang, Hanyun;AbdulJabbar, Khalid;Pan, Xiaoxi;Yuan, Yinyin;Chuter, David;MacKenzie, Mairead;Chee, Serena;Alzetani, Aiman;Scarlett, Lydia;Richards, Jennifer;Ingram, Papawadee;Austin, Silvia;De Sousa, Paulo;Jordan, Simon;Rice, Alexandra;Raubenheimer, Hilgardt;Bhayani, Harshil;Ambrose, Lyn;Devaraj, Anand;Chavan, Hema;Begum, Sofina;Buderi, Silviu, I;Kaniu, Daniel;Malima, Mpho;Booth, Sarah;Fernandes, Nadia;Shah, Pratibha;Proli, Chiara;Danson, Sarah;Robinson, Lily;Dick, Craig;Kirk, Alan;Asif, Mo;Bilancia, Rocco;Kostoulas, Nikos;Thomas, Mathew
通讯作者：
Thomas, Mathew
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
影响因子：
28.4
作者：
Garcia-Murillas, Isaac;Chopra, Neha;Turner, Nicholas C.
通讯作者：
Turner, Nicholas C.
影响因子：
46.9
作者：
Cohen JD;Douville C;Dudley JC;Mog BJ;Popoli M;Ptak J;Dobbyn L;Silliman N;Schaefer J;Tie J;Gibbs P;Tomasetti C;Papadopoulos N;Kinzler KW;Vogelstein B
通讯作者：
Vogelstein B