Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

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

doi:10.1038/nature22364

Cited by 1,290 publications

(1,407 citation statements)

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“…In addition, circulating tumor DNA (ctDNA) may be undetectable when shedding of tumor DNA is nominal, such as when therapy stabilizes tumor growth (7,8). Recent efforts to globally characterize tumor heterogeneity using both plasma cfDNA analysis and multi-region tumor sequencing highlight the complementary nature of the two approaches (9)(10)(11). However, there is a paucity of cfDNA data sets large enough to evaluate the similarity of tumor-initiating alterations ("truncal drivers") in solid tumor cancers to those found in the cfDNA of advanced cancer patients.…”

Section: Introductionmentioning

confidence: 99%

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Zill

Banks

Fairclough

et al. 2018

Clinical Cancer Research

283

223

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Running title: Somatic genomic landscape of circulating tumor DNA Keywords: circulating tumor DNA, tumor heterogeneity, resistance, genomic landscape, cfDNA clonality Financial support: The study was funded by and conducted at Guardant Health, Inc. No additional grant support or administrative support was provided for the study. *Corresponding author:Stephen R. Fairclough Translational relevanceThis study describes genomic alterations from the largest cell-free circulating tumor DNA cohort to date, as derived from regular clinical practice. The high prevalence of resistance alterations found in advanced, treated cancer patients necessitated accurate methods for determining mutation clonality and driver/resistance status from plasma. We provide such methods, thereby extending the utility of cell-free DNA sequencing analysis. Our finding of an association between estimated circulating tumor DNA (ctDNA) levels and tumor mutational burden ascertained from plasma suggests that ctDNA level is likely an important variable to consider for immunotherapy applications of ctDNA analysis. Although cell-free DNA can provide a summary of tumor heterogeneity across multiple metastatic sites in a patient, our findings of high variability in ctDNA levels across patients, and its impact on variant detection, highlight the need for an improved understanding of factors influencing ctDNA levels and safe methods for maximizing them at the time of ctDNA testing. AbstractPurpose: Cell-free DNA (cfDNA) sequencing provides a non-invasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants.Experimental Design: We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. To facilitate interpretation of the genomic complexity of circulating tumor DNA in advanced, treated cancer patients, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality.Results: Patterns and prevalence of cfDNA alterations in major driver genes for non-small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (TCGA and COSMIC;, with the principle differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naïve tumors. Upon applying novel cfDNA clonality and copy-number driver identification methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations (FDR=5x10 -7 for EGFR and ERBB2), in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel ...

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Section: Introductionmentioning

confidence: 99%

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Zill

Banks

Fairclough

et al. 2018

Clinical Cancer Research

283

223

View full text Add to dashboard Cite

show abstract

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This multiregional analysis (MRA) sequencing approach enabled us not only to observe spatial heterogeneity, but also to calculate temporal alterations and eventually disclose the evolution of tumors. There are two types of somatic aberration in a tumor: ubiquitous aberrations (founder mutations, trunk mutations, or clonal mutations) and scattered aberrations (progressor mutations, branch/leaf mutations, or subclonal mutations).…”

Section: Introductionmentioning

confidence: 99%

Cancer evolution and heterogeneity

Mimori

Saito

Niida

et al. 2018

Annals of Gastroent Surgery

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Undoubtedly, intratumor heterogeneity (ITH) is one of the causes of the intractability of cancers. Recently, technological innovation in genomics has promoted studies on ITH in solid tumors and on the pattern and level of diversity, which varies among malignancies. We profiled the genome in multiple regions of nine colorectal cancer (CRC) cases. The most impressive finding was that in the late phase, a parental clone branched into numerous subclones. We found that minor mutations were dominant in advanced CRC named neutral evolution; that is, driver gene aberrations were observed with high proportion in the early‐acquired phase, but low in the late‐acquired phase. Then, we validated that neutral evolution could cause ITH in advanced CRC by super‐computational analysis. According to the clinical findings, we explored a branching evolutionary process model in cancer evolution, which assumes that each tumor cell has cellular automaton. According to the model, we verified factors to foster ITH with neutral evolution in advanced CRC. In this review, we introduce recent advances in the field of ITH including the general component of ITH, clonal selective factors that consolidate the evolutionary process, and a representative clinical application of ITH.

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“…The plasma of the first 100 patients enrolled in TRACERx and 1 patient co-recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) were collected and analyzed in order to correlate ctDNA release, their level in plasma at the time of surgery and in the follow-up time, with recurrence risk, chemotherapy resistance and death. The clear benefit of this technique is to monitor ctDNA profile with a no invasive method in order to guarantee an accurate detection of preclinical recurrence and to intervene earlier with new therapeutic strategy to eradicate tumors as first biomolecular appearance (6).…”

Section: Editorial On Thoracic Surgerymentioning

confidence: 99%