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J Hematol Oncol. 2017 May 4;10(1):100. doi: 10.1186/s13045-017-0468-1.

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages.

Yang M1,2,3,4, Topaloglu U1,2,4, Petty WJ1,5,4, Pagni M1,6,4, Foley KL1,7,4, Grant SC1,5,4, Robinson M1,4, Bitting RL1,5,4, Thomas A1,5,4, Alistar AT1,5,4, Desnoyers RJ1,5,4, Goodman M1,5,4, Albright C1,5,4, Porosnicu M1,5,4, Vatca M1,5,4, Qasem SA1,8,4, DeYoung B1,8,4, Kytola V1,2,9,4, Nykter M9, Chen K3, Levine EA1,10,4, Staren ED1,10,4, D'Agostino RB Jr1,11,4, Petro RM1,5,4, Blackstock W1,12,4, Powell BL1,5,4, Abraham E1,2,4, Pasche B13,14,15,16, Zhang W17,18,19,20,21.

Author information

1
Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC, 27157, USA.
2
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
3
Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
4
Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
5
Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
6
Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
7
Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
8
Department of Laboratory Medicine and Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
9
Institute for Biosciences and Medical Technology, University of Tampere, 33520, Tampere, Finland.
10
Department of General Surgery-Section of Surgical Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
11
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
12
Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
13
Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC, 27157, USA. bpasche@wakehealth.edu.
14
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. bpasche@wakehealth.edu.
15
Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. bpasche@wakehealth.edu.
16
Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. bpasche@wakehealth.edu.
17
Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC, 27157, USA. wezhang@wakehealth.edu.
18
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. wezhang@wakehealth.edu.
19
Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. wezhang@wakehealth.edu.
20
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. wezhang@wakehealth.edu.
21
Cancer Genomics and Precision Medicine, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, 27157, USA. wezhang@wakehealth.edu.

Abstract

BACKGROUND:

Solid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs) and circulating tumor DNAs (ctDNA). Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches.

METHODS:

We isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments.

RESULTS:

Mutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II) and late stage (III and IV) cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177) of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that are consistent with cancer progression or response to EGFR drug treatment.

CONCLUSIONS:

This study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution.

KEYWORDS:

Clonality; Liquid biopsy; Lung cancer; Mutation rate; Non-invasive

PMID:
28472989
PMCID:
PMC5418716
DOI:
10.1186/s13045-017-0468-1
[Indexed for MEDLINE]
Free PMC Article

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