Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages
| العنوان: | Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages |
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| المؤلفون: | Stefan C. Grant, Bayard L. Powell, Edward Abraham, Matthew Pagni, Kristie L. Foley, Angela Tatiana Alistar, Shadi Qasem, Ville Kytölä, Michael Goodman, Edward A. Levine, Mac B. Robinson, Umit Topaloglu, Robin M. Petro, Barry DeYoung, Rhonda L. Bitting, Alexandra Thomas, Kexin Chen, Matti Nykter, Meng Yang, Wei Zhang, Rodwige J. Desnoyers, Mihaela Vatca, William Blackstock, Carol A. Albright, Mercedes Porosnicu, Ralph B. D'Agostino, Edgar D. Staren, W. Jeffrey Petty, Boris Pasche |
| المصدر: | Journal of Hematology & Oncology, Vol 10, Iss 1, Pp 1-13 (2017) Journal of Hematology & Oncology |
| بيانات النشر: | BMC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Cancer Research, Mutation rate, Lung Neoplasms, medicine.disease_cause, 0302 clinical medicine, Circulating tumor cell, Neoplasms, Non-invasive, Aged, 80 and over, Mutation, Smoking, Chemoradiotherapy, DNA, Neoplasm, Hematology, lcsh:Diseases of the blood and blood-forming organs, Middle Aged, Neoplastic Cells, Circulating, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Neoplasm Proteins, 3. Good health, ErbB Receptors, Oncology, 030220 oncology & carcinogenesis, Disease Progression, Neoplastic Stem Cells, Female, KRAS, Lung cancer, Adult, DNA repair, Antineoplastic Agents, Biology, lcsh:RC254-282, Erlotinib Hydrochloride, 03 medical and health sciences, medicine, Humans, Neoplasm Invasiveness, Liquid biopsy, Protein Kinase Inhibitors, Molecular Biology, Aged, Retrospective Studies, lcsh:RC633-647.5, Research, Gene Expression Profiling, Cancer, Genes, erbB-1, Sequence Analysis, DNA, Genes, p53, medicine.disease, Clone Cells, Genes, ras, 030104 developmental biology, Immunology, Cancer research, Genes, Neoplasm, Clonality |
| الوصف: | 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. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0468-1) contains supplementary material, which is available to authorized users. |
| اللغة: | English |
| تدمد: | 1756-8722 |
| DOI: | 10.1186/s13045-017-0468-1 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a042f75f31d479fbd7ad8eff0e1a3dc0 http://link.springer.com/article/10.1186/s13045-017-0468-1 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a042f75f31d479fbd7ad8eff0e1a3dc0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17568722 |
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| DOI: | 10.1186/s13045-017-0468-1 |