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Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

2017; Nature Portfolio; Volume: 545; Issue: 7655 Linguagem: Inglês

10.1038/nature22364

1476-4687

Christopher Abbosh, Nicolai J. Birkbak, Gareth A. Wilson, Mariam Jamal‐Hanjani, T Constantin, Raheleh Salari, John Le Quesne, David A. Moore, Selvaraju Veeriah, Rachel Rosenthal, Teresa Marafioti, Eser Kırkızlar, Anne Thomas, Nicholas McGranahan, Sophia Ward, Luke Martinson, Joan Riley, Francesco Fraioli, Maise Al Bakir, Eva Grönroos, Francisco Zambrana, Raymondo Endozo, Wenya Linda Bi, Fiona M. Fennessy, Nicole Sponer, Diana Johnson, Joanne Laycock, Seema Shafi, Justyna Czyzewska-Khan, Andrew Rowan, Tim Chambers, Nik Matthews, Samra Turajlic, Crispin T. Hiley, SM Lee, Martin Förster, Tanya Ahmad, Mary Falzon, Elaine Borg, David Lawrence, Sophia Ward, Shyam Kolvekar, Nikolaos Panagiotopoulos, Sam M. Janes, Ricky M. Thakrar, Asia Ahmed, Fiona Blackhall, Yvonne Summers, Dina Hafez, Ashwini Naik, Apratim Ganguly, Stephanie Kareht, Rajesh Shah, Leena Dennis Joseph, Anne Marie Quinn, Philip Crosbie, Babu Naidu, Gary Middleton, Gerald Langman, Simon Trotter, M. Nicolson, Hardy Remmen, Keith M. Kerr, Mahendran Chetty, Lesley Gomersall, Dean A. Fennell, Apostolos Nakas, Sridhar Rathinam, Girija Anand, Sajid Khan, Peter Russell, Veni Ezhil, Babikir Ismail, Melanie Irvin-Sellers, Vineet Prakash, J.F. Lester, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Dahmane Oukrif, Ayse U. Akarca, John A. Hartley, Helen L. Lowe, Sara Lock, Natasha Iles, Harriet Bell, Yenting Ngai, Greg Elgar, Zoltán Szállási, Roland F. Schwarz, Javier Herrero, Grant D. Stewart, Sergio A. Quezada, Karl S. Peggs, Peter Van Loo, Caroline Dive, C Jimmy Lin, Matthew Rabinowitz, Hugo J.W.L. Aerts, Allan Hackshaw, Jacqui Shaw, Bernhard Zimmermann, Charles Swanton,

Genetic factors in colorectal cancer

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies. Circulating tumour DNA profiling in early-stage non-small-cell lung cancer can be used to track single-nucleotide variants in plasma to predict lung cancer relapse and identify tumour subclones involved in the metastatic process. Circulating tumour DNA (ctDNA) has proven useful for detecting and monitoring cancer progression from plasma samples. The authors have applied a bespoke multiplex-PCR next-generation sequencing approach to profile ctDNA in the prospective TRACERx lung cancer clinical trial study. The assay tracks clonal and subclonal variants, in pre- and post-surgery samples. In pre-surgery samples ctDNA detection is associated with histological subtype and other pathological variables and correlates with tumour volume. Blinded longitudinal profiling suggests that ctDNA detection also associates with relapse, and provides insight into the evolutionary patterns of tumour cell subclones during progression. These results advance our understanding of how liquid biopsies can be applied clinically to improve monitoring of cancer.