Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing

Our plain-English summary of Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing, by S. Mäki-Nevala, V.K. Sarhadi, A. Knuuttila, et al (Lung, 2016).

The study

• Authors: S. Mäki-Nevala, V.K. Sarhadi, A. Knuuttila, I. Scheinin, P. Ellonen, S. Lagström, M. Rönty, E. Kettunen, K. Husgafvel-Pursiainen, H. Wolff, S. Knuutila
• Journal: Lung
• Published: 2016;194(1):125-35
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Asbestos is a carcinogen linked to malignant mesothelioma (MM) and lung cancer. Some gene aberrations related to asbestos exposure are recognized, but many associated mutations remain obscure. We performed exome sequencing to determine the association of previously known mutations (driver gene mutations) with asbestos and to identify novel mutations related to asbestos exposure in lung adenocarcinoma (LAC) and MM.

Methods: Exome sequencing was performed on DNA from 47 tumor tissues of MM (21) and LAC (26) patients, 27 of whom had been asbestos-exposed (18 MM, 9 LAC). In addition, 9 normal lung/blood samples of LAC were sequenced. Novel mutations identified from exome data were validated by amplicon-based deep sequencing. Driver gene mutations in BRAF, EGFR, ERBB2, HRAS, KRAS, MET, NRAS, PIK3CA, STK11, and ephrin receptor genes (EPHA1-8, 10 and EPHB1-4, 6) were studied for both LAC and MM, and in BAP1, CUL1, CDKN2A, and NF2 for MM.

Results: In asbestos-exposed MM patients, previously non-described NF2 frameshift mutation (one) and BAP1 mutations (four) were detected. Exome data mining revealed some genes potentially associated with asbestos exposure, such as MRPL1 and SDK1. BAP1 and COPG1 mutations were seen exclusively in MM. Pathogenic KRAS mutations were common in LAC patients (42 %), both in non-exposed (n = 5) and exposed patients (n = 6). Pathogenic BRAF mutations were found in two LACs.

Conclusion: BAP1 mutations occurred in asbestos-exposed MM. MRPL1, SDK1, SEMA5B, and INPP4A could possibly serve as candidate genes for alterations associated with asbestos exposure. KRAS mutations in LAC were not associated with asbestos exposure.

In plain English

This laboratory study from Helsinki, Finland, used exome sequencing, which reads the protein-coding parts of DNA, to look for gene mutations in tumor samples. The samples came from 21 people with malignant mesothelioma (19 pleural, 2 peritoneal) and 26 people with lung adenocarcinoma. Patients were classed as asbestos-exposed or not by counting asbestos fibers in their lung tissue. By that measure, 18 mesothelioma and 9 adenocarcinoma patients were exposed. The article does not name fiber types. A previously undescribed MRPL1 mutation was found in three exposed patients (2 mesothelioma, 1 adenocarcinoma). It was not seen in any non-exposed sample. BAP1 mutations were found in four mesothelioma patients, all exposed. KRAS mutations appeared in 11 of 26 adenocarcinomas (42%): 6 in exposed and 5 in non-exposed patients. The authors concluded that MRPL1, SDK1, SEMA5B and INPP4A could possibly be candidate genes for asbestos-related changes, and that KRAS mutations were not associated with asbestos exposure. They noted three limits. The small sample gave no statistical significance. Few non-exposed mesothelioma cases were available. For most candidate mutations, they could not confirm whether the mutation arose in the tumor.

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: exome sequencing of tumor DNA, comparing asbestos-exposed and non-exposed patients, with selected mutations checked by amplicon-based deep sequencing
• Who was studied: 47 Finnish patients diagnosed and operated on in the Hospital District of Helsinki and Uusimaa. There were 21 with epithelioid malignant mesothelioma (19 pleural, 2 peritoneal; 18 asbestos-exposed) and 26 with lung adenocarcinoma (9 asbestos-exposed). Normal tissue from 9 of the adenocarcinoma patients was also sequenced.
• Exposure: Asbestos fiber concentration in lung tissue, measured by electron microscopy; fiber types are not specified. Exposed patients' ranges were 2.1 to 1300 million fibers per gram of dry lung tissue (mesothelioma) and 2.1 to 72.9 (adenocarcinoma). Non-exposed ranges were below 0.2 (mesothelioma) and 0.0 to 0.3 (adenocarcinoma).
• Main results:
  • A recurrent, previously undescribed MRPL1 mutation (Tyr87Cys) was found in three asbestos-exposed patients (2 mesothelioma, 1 lung adenocarcinoma). It was not seen in non-exposed samples or paired normal samples.
  • In mesothelioma, BAP1 mutations were found in four patients, all asbestos-exposed.
  • Deep sequencing showed the BAP1 mutations to be somatic (present in the tumor but not in the same patient's normal tissue). For one of the four patients no normal tissue was available, but the mutation was reproduced in the tumor.
  • A single nucleotide deletion in the NF2 gene was found in one asbestos-exposed mesothelioma patient.
  • One somatic SDK1 mutation (Gln963Ter) was found in an asbestos-exposed lung adenocarcinoma patient.
  • KRAS mutations were found in 11 of 26 lung adenocarcinomas (42%).
  • Of the lung adenocarcinoma patients with KRAS mutations, 6 were asbestos-exposed and 5 were non-exposed.
  • BRAF mutations were found in two lung adenocarcinoma patients, both non-exposed.
  • Ephrin receptor gene mutations were seen in both exposed and non-exposed patients.
• The authors' conclusion: The authors concluded that BAP1 mutations occurred in asbestos-exposed mesothelioma. They also concluded that MRPL1, SDK1, SEMA5B and INPP4A could possibly serve as candidate genes for alterations associated with asbestos exposure, and that KRAS mutations in lung adenocarcinoma were not associated with asbestos exposure.
• Limitations the authors state:
  • The sample was small, so no statistical significance was found. Recurrent variants were therefore defined simply as those seen in three or more exposed patients.
  • Non-exposed mesothelioma cases are very hard to obtain. So although all BAP1 and COPG1 mutations were in exposed mesothelioma patients, the authors could not conclude that these mutations are exclusively associated with asbestos exposure.
  • Normal tissue was lacking and deep sequencing had technical difficulties, so it remains unclear whether the other candidate mutations arose in the tumor (somatic).

Topics

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

Medical terms in this study, explained in our Lexicon: Lung Adenocarcinoma, Malignant Mesothelioma, Lung Cancer, Asbestos Exposure, EGFR, BAP1, CDKN2A.

Related studies

• Whole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma: A case report — I. Vanni, S. Coco, et al. (2016)
• Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas — H.C. Kang, H.K. Kim, et al. (2016)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)
• Establishment and mutation analysis of a novel malignant peritoneal mesothelioma cell line, TU-MM-1, using whole genome sequencing — N. Oumi, H. Itamochi, et al. (2016)
• Association between lung cancer somatic mutations and occupational exposure in never-smokers — C. Paris, P. Do, et al. (2017)
• Epidermal growth factor receptor mutations in 510 Finnish non--small-cell lung cancer patients — S. Mäki-Nevala, M. Rönty, et al. (2014)

Browse more research in Lung, or return to medical research.