Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing
- 906 Downloads
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.
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.
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.
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.
KeywordsAsbestos Mutation Lung adenocarcinoma Mesothelioma Exome sequencing
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).
Compliance with Ethical Standards
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.
- 1.IARC (2012) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Arsenic, metals, fibres and dusts, A review of human carcinogens, p 100CGoogle Scholar
- 2.Kane A, Jean D, Knuutila S et al (2014) Malignant mesothelioma: mechanism of carcinogenesis. In: Anttila S, Boffetta P (eds) Occupational cancers. Springer, London, p 299Google Scholar
- 5.Kettunen E, Knuutila S (2014) Malignant mesothelioma: molecular markers. In: Anttila S, Boffetta P (eds) Occupational cancers. Springer, London, p 325Google Scholar
- 17.Tuononen K, Maki-Nevala S, Sarhadi VK et al (2013) Comparison of targeted next-generation sequencing (NGS) and real-time PCR in the detection of EGFR, KRAS, and BRAF mutations on formalin-fixed, paraffin-embedded tumor material of non-small cell lung carcinoma-superiority of NGS. Genes Chromosom Cancer 52:503–511. doi: 10.1002/gcc.22047 CrossRefPubMedGoogle Scholar
- 18.Sulonen AM, Ellonen P, Almusa H et al (2011) Comparison of solution-based exome capture methods for next generation sequencing. Genome Biol 12:R94-2011-12-9-r94, DOI: 10.1186/gb-2011-12-9-r94
- 19.St John J SeqPrep. https://github.com/jstjohn/SeqPrep
- 22.BCFTools. http://samtools.github.io/bcftools/
- 27.Maki-Nevala S, Kaur Sarhadi V, Tuononen K et al (2013) Mutated ephrin receptor genes in non-small cell lung carcinoma and their occurrence with driver mutations-targeted resequencing study on formalin-fixed, paraffin-embedded tumor material of 81 patients. Genes Chromosom Cancer 52:1141–1149. doi: 10.1002/gcc.22109 CrossRefPubMedGoogle Scholar