Tumor-specific genetic variants can be detected in circulating cell-free DNA of malignant pleural mesothelioma patients

Our plain-English summary of Tumor-specific genetic variants can be detected in circulating cell-free DNA of malignant pleural mesothelioma patients, by M. Hylebos, K. Op de Beeck, P. Pauwels, et al (Lung Cancer, 2018).

The study

• Authors: M. Hylebos, K. Op de Beeck, P. Pauwels, K. Zwaenepoel, J.P. van Meerbeeck, G. Van Camp
• Journal: Lung Cancer
• Published: 2018;124:19-22
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Patients diagnosed with malignant pleural mesothelioma (MPM) face a poor prognosis, with an overall survival plateauing at a median of one year. This can be explained by difficulties in early diagnosis, effective treatment and treatment monitoring. Circulating cell-free tumor DNA (ctDNA) is emerging as an interesting biomarker addressing some of these issues. So far, the development of ctDNA in MPM lags behind that in other tumors. In this study, the possibility of tracing tumor-specific genetic variants, identified in MPM tissue, in circulating DNA of the corresponding patients is investigated.

Materials And Methods: Whole exome sequencing was performed on paired tumor and germline DNA of ten MPM patients, of which five were treatment naïve. For each patient, a tumor-specific variant was selected and traced in tumor, germline and circulating DNA using droplet digital PCR in two independent runs.

Results: All but one tumor-specific variants, selected after whole exome sequencing, were validated on primary tumor tissue using droplet digital PCR analysis. Patient-specific, selected variants could be detected in circulating DNA of three MPM patients, either in one or both independent droplet digital PCR runs. Mutated fractions in circulating DNA ranged from 0.28 to 0.9%. Interestingly, all patients whose circulating DNA samples contained tumor-specific variants, were treatment naïve.

Conclusion: We demonstrated for the first time the presence of ctDNA within circulating DNA of treatment naïve MPM patients. This finding opens perspectives towards the use of ctDNA as a biomarker for (early and differential) diagnosis, treatment and treatment monitoring of MPM, which all remain challenging.

Copyright © 2018 Elsevier B.V. All rights reserved.

In plain English

This laboratory study from Antwerp, Belgium, asked whether genetic changes found in malignant pleural mesothelioma tumors could also be found in DNA circulating freely in the blood of the same patients. The authors used stored tumor, blood-cell and plasma samples from ten patients. Five were untreated when sampled; the rest had received chemotherapy. The authors sequenced tumor and normal DNA, chose one tumor-specific change per patient, and searched for it in plasma DNA using a sensitive test run twice. All but one chosen change was confirmed in the tumors. The change was found in plasma DNA of three of the ten patients, at fractions of 0.28 to 0.9%. For one patient it appeared in both runs; for the other two, in only one run. All three were untreated, giving a detection rate of three out of five untreated patients. The selected change was not detected in the plasma DNA of any patient treated with chemotherapy before sampling. The authors concluded this was proof of concept that tumor DNA is present in the blood of untreated patients. They noted that evidence for using it to monitor treatment remains insufficient. Asbestos exposure was not examined.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory genetic study of stored patient samples: whole exome sequencing of paired tumor and germline DNA, followed by droplet digital PCR testing of circulating cell-free DNA
• Who was studied: Ten malignant pleural mesothelioma patients, five of them treatment naïve at the time of sampling. Samples were provided by Biobank@UZA, Antwerp, Belgium. Sampling dates are not given in the text.
• Exposure: No asbestos or other environmental exposure was studied. The study examined tumor-specific genetic variants. The patients who were not treatment naïve had received prior chemotherapy.
• Main results:
  • In the ten tumors, BAP1 mutations were found in 50% and NF2 mutations in 30%.
  • All selected tumor-specific variants were confirmed in tumor DNA except the NF2 variant of patient 5.
  • The selected variants were detected in circulating cell-free DNA of three out of ten patients, with allelic fractions ranging from 0.28 to 0.9%.
  • Patient 1's NF2 variant was seen in the cfDNA sample in both runs, at 0.8 and 0.9%. Variants of patients 2 and 3 were detected in only one of two runs, at 0.28% and 0.33% respectively.
  • In tumor DNA, the mutated fraction was 44.6 and 42.7% for patient 1, 12.9 and 13.4% for patient 2, and 9.9 and 10.6% for patient 3.
  • All three patients with detected variants were treatment naïve, a detection rate of 60% (three out of five) among untreated patients.
  • The selected variants were not detected in the cfDNA of any patient who had received chemotherapy before sample collection.
• The authors' conclusion: The authors concluded that the study provided proof of concept that circulating tumor DNA is present in the blood of treatment naïve malignant pleural mesothelioma patients.
• Limitations the authors state:
  • The authors noted there is still insufficient solid evidence on the clinical validity and usefulness of ctDNA for monitoring treatment response, and that larger prospective studies are required.
  • The NF2 variant of patient 5 was not confirmed when tested on a different set of tumor sections, which the authors said hints at tumor heterogeneity.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Overall Survival, ctDNA, Biomarker.

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