Circulating mutational portrait of cancer

Manifestation of aggressive clonal events in both early and late stages

Meng Yang, Umit Topaloglu, W. Jeffrey Petty, Matthew Pagni, Kristie L. Foley, Stefan C. Grant, Mac Robinson, Rhonda L. Bitting, Alexandra Thomas, Angela Alistar, Rodwige J. Desnoyers, Michael Goodman, Carol Albright, Mercedes Porosnicu, Mihaela Vatca, Shadi A. Qasem, Barry Deyoung, Ville Kytola, Matti Nykter, Kexin Chen & 9 others Edward A. Levine, Edgar D. Staren, Ralph B. D'Agostino, Robin M. Petro, William Blackstock, Bayard L. Powell, Edward Abraham, Boris Pasche, Wei Zhang

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Article number100
JournalJournal of Hematology and Oncology
Volume10
Issue number1
DOIs
StatePublished - May 4 2017

Fingerprint

Neoplasms
Mutation
DNA
Mutation Rate
Lung Neoplasms
Clone Cells
BRCA2 Gene
BRCA1 Gene
Genes
erbB-1 Genes
Circulating Neoplastic Cells
High-Throughput Nucleotide Sequencing
DNA Fingerprinting
Mortality
DNA Sequence Analysis
Early Detection of Cancer
DNA Repair
Pharmaceutical Preparations
Radiotherapy
Smoking

All Science Journal Classification (ASJC) codes

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Yang, Meng ; Topaloglu, Umit ; Petty, W. Jeffrey ; Pagni, Matthew ; Foley, Kristie L. ; Grant, Stefan C. ; Robinson, Mac ; Bitting, Rhonda L. ; Thomas, Alexandra ; Alistar, Angela ; Desnoyers, Rodwige J. ; Goodman, Michael ; Albright, Carol ; Porosnicu, Mercedes ; Vatca, Mihaela ; Qasem, Shadi A. ; Deyoung, Barry ; Kytola, Ville ; Nykter, Matti ; Chen, Kexin ; Levine, Edward A. ; Staren, Edgar D. ; D'Agostino, Ralph B. ; Petro, Robin M. ; Blackstock, William ; Powell, Bayard L. ; Abraham, Edward ; Pasche, Boris ; Zhang, Wei. / Circulating mutational portrait of cancer : Manifestation of aggressive clonal events in both early and late stages. In: Journal of Hematology and Oncology. 2017 ; Vol. 10, No. 1.
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title = "Circulating mutational portrait of cancer: Manifestation of aggressive clonal events in both early and late stages",
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.",
author = "Meng Yang and Umit Topaloglu and Petty, {W. Jeffrey} and Matthew Pagni and Foley, {Kristie L.} and Grant, {Stefan C.} and Mac Robinson and Bitting, {Rhonda L.} and Alexandra Thomas and Angela Alistar and Desnoyers, {Rodwige J.} and Michael Goodman and Carol Albright and Mercedes Porosnicu and Mihaela Vatca and Qasem, {Shadi A.} and Barry Deyoung and Ville Kytola and Matti Nykter and Kexin Chen and Levine, {Edward A.} and Staren, {Edgar D.} and D'Agostino, {Ralph B.} and Petro, {Robin M.} and William Blackstock and Powell, {Bayard L.} and Edward Abraham and Boris Pasche and Wei Zhang",
year = "2017",
month = "5",
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doi = "10.1186/s13045-017-0468-1",
language = "English (US)",
volume = "10",
journal = "Journal of Hematology and Oncology",
issn = "1756-8722",
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Yang, M, Topaloglu, U, Petty, WJ, Pagni, M, Foley, KL, Grant, SC, Robinson, M, Bitting, RL, Thomas, A, Alistar, A, Desnoyers, RJ, Goodman, M, Albright, C, Porosnicu, M, Vatca, M, Qasem, SA, Deyoung, B, Kytola, V, Nykter, M, Chen, K, Levine, EA, Staren, ED, D'Agostino, RB, Petro, RM, Blackstock, W, Powell, BL, Abraham, E, Pasche, B & Zhang, W 2017, 'Circulating mutational portrait of cancer: Manifestation of aggressive clonal events in both early and late stages', Journal of Hematology and Oncology, vol. 10, no. 1, 100. https://doi.org/10.1186/s13045-017-0468-1

Circulating mutational portrait of cancer : Manifestation of aggressive clonal events in both early and late stages. / Yang, Meng; Topaloglu, Umit; Petty, W. Jeffrey; Pagni, Matthew; Foley, Kristie L.; Grant, Stefan C.; Robinson, Mac; Bitting, Rhonda L.; Thomas, Alexandra; Alistar, Angela; Desnoyers, Rodwige J.; Goodman, Michael; Albright, Carol; Porosnicu, Mercedes; Vatca, Mihaela; Qasem, Shadi A.; Deyoung, Barry; Kytola, Ville; Nykter, Matti; Chen, Kexin; Levine, Edward A.; Staren, Edgar D.; D'Agostino, Ralph B.; Petro, Robin M.; Blackstock, William; Powell, Bayard L.; Abraham, Edward; Pasche, Boris; Zhang, Wei.

In: Journal of Hematology and Oncology, Vol. 10, No. 1, 100, 04.05.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Circulating mutational portrait of cancer

T2 - Manifestation of aggressive clonal events in both early and late stages

AU - Yang, Meng

AU - Topaloglu, Umit

AU - Petty, W. Jeffrey

AU - Pagni, Matthew

AU - Foley, Kristie L.

AU - Grant, Stefan C.

AU - Robinson, Mac

AU - Bitting, Rhonda L.

AU - Thomas, Alexandra

AU - Alistar, Angela

AU - Desnoyers, Rodwige J.

AU - Goodman, Michael

AU - Albright, Carol

AU - Porosnicu, Mercedes

AU - Vatca, Mihaela

AU - Qasem, Shadi A.

AU - Deyoung, Barry

AU - Kytola, Ville

AU - Nykter, Matti

AU - Chen, Kexin

AU - Levine, Edward A.

AU - Staren, Edgar D.

AU - D'Agostino, Ralph B.

AU - Petro, Robin M.

AU - Blackstock, William

AU - Powell, Bayard L.

AU - Abraham, Edward

AU - Pasche, Boris

AU - Zhang, Wei

PY - 2017/5/4

Y1 - 2017/5/4

N2 - 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.

AB - 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.

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