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

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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.

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Acknowledgments

We thank Päivi Tuominen, Jaana Kierikki, Helinä Hämäläinen, Sauli Savukoski, Tuula Suitiala, Finnish Institute of Occupational Health, and Milja Tikkanen and Tiina Wirtanen, University of Helsinki, for excellent technical assistance. We are also grateful to Ewen MacDonald for the correction of grammar and style. This work was funded by the Finnish Work Environment Fund (no. 112268 to SK; 112269 to HW; 111100 to KHP), Sigrid Jusélius Foundation, Cancer Society of Finland (11/13/2013 to SK; 11/12/2014 to KHP).

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Authors and Affiliations

  1. Department of Pathology, Faculty of Medicine, University of Helsinki, P.O. Box 21, 00014, Helsinki, Finland

    Satu Mäki-Nevala, Virinder Kaur Sarhadi, Ilari Scheinin & Sakari Knuutila

  2. Department of Pulmonary Medicine, Heart and Lung Center, University of Helsinki and Helsinki University Hospital, P.O. Box 340, 00029, Helsinki, Finland

    Aija Knuuttila

  3. VU University Medical Center, De Boelelaan 1118, 1081 HZ, Amsterdam, The Netherlands

    Ilari Scheinin

  4. Sequencing Unit, Institute for Molecular Medicine Finland, BM2U, Tukholmankatu 8, 00029, Helsinki, Finland

    Pekka Ellonen & Sonja Lagström

  5. HUSLAB, Department of Pathology, Helsinki University Central Hospital, P.O. Box 400, 00029, Helsinki, Finland

    Mikko Rönty

  6. Finnish Institute of Occupational Health, P.O. Box 40, 00251, Helsinki, Finland

    Eeva Kettunen, Kirsti Husgafvel-Pursiainen & Henrik Wolff

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  1. Satu Mäki-Nevala
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Correspondence to Sakari Knuutila.

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Conflicts of interest

Aija Knuuttila received payment for consultancy from Pfizer, Boehringer-Ingelheim, Roche, BMS and for lectures, including service on speakers bureaus, from Pfizer, Lilly, BMS. All other authors declare that they do not have any conflict of interest.

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Mäki-Nevala, S., Sarhadi, V.K., Knuuttila, A. et al. Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing. Lung 194, 125–135 (2016). https://doi.org/10.1007/s00408-015-9814-7

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