Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

Abstract

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.

• Authors: Christopher Abbosh, Nicolai J Birkbak, Gareth A Wilson, Mariam Jamal-Hanjani, Tudor Constantin, Raheleh Salari, John Le Quesne, David A Moore, Selvaraju Veeriah, Rachel Rosenthal, Teresa Marafioti, Eser Kirkizlar, Thomas B K Watkins, 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 Hiley, Siow Ming Lee, Martin D Forster, Tanya Ahmad, Mary Falzon, Elaine Borg, David Lawrence, Martin Hayward, Shyam Kolvekar, Nikolaos Panagiotopoulos, Sam M Janes, Ricky Thakrar, Asia Ahmed, Fiona Blackhall, Yvonne Summers, Dina Hafez, Ashwini Naik, Apratim Ganguly, Stephanie Kareht, Rajesh Shah, Leena Joseph, Anne Marie Quinn, Phil A Crosbie, Babu Naidu, Gary Middleton, Gerald Langman, Simon Trotter, Marianne Nicolson, Hardy Remmen, Keith 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, Jason 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, Zoltan Szallasi, Roland F Schwarz, Javier Herrero, Aengus 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 A Shaw, Bernhard G Zimmermann, TRACERx consortium, PEACE consortium, Charles Swanton
• Journal: Nature (Nature) Vol. 545 Issue 7655 Pg. 446-451 (04 26 2017) ISSN: 1476-4687 [Electronic] England
• PMID: 28445469 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Neoplasm

Topics

• Biopsy (methods)
• Carcinoma, Non-Small-Cell Lung (blood, genetics, pathology, surgery)
• Cell Lineage (genetics)
• Cell Tracking
• Clone Cells (metabolism, pathology)
• DNA Mutational Analysis
• DNA, Neoplasm (blood, genetics)
• Disease Progression
• Drug Resistance, Neoplasm (genetics)
• Early Detection of Cancer (methods)
• Evolution, Molecular
• Humans
• Limit of Detection
• Lung Neoplasms (blood, genetics, pathology, surgery)
• Multiplex Polymerase Chain Reaction
• Neoplasm Metastasis (diagnosis, genetics, pathology)
• Neoplasm Recurrence, Local (diagnosis, genetics, pathology)
• Postoperative Care (methods)
• Reproducibility of Results
• Tumor Burden