Abstract
Lung carcinoids are rare neuroendocrine tumors of the lung. Very little is known about the genetic background of these tumors. We applied Ion Torrent Ampliseq next-generation technology to study hotspot mutations of 22 lung cancer-related genes from typical and atypical lung carcinoid tumors. DNA isolated from 25 formalin-fixed, paraffin-embedded carcinoid tumors were amplified to prepare barcoded libraries covering 507 mutations included in 90 amplicons. The libraries were pooled, purified, enriched, and sequenced on ion personal genome machine. The sequences were aligned and checked for known and novel variations using Torrent Suite Software v.4.0.2. One out of 25 patients had mutations in the targeted regions sequenced. This patient had mutations in BRAF, SMAD4, PIK3CA, and KRAS. All these mutations were confirmed as somatic and are previously known mutations. In summary, mutations in genes commonly mutated in non-small-cell lung cancer are not common in lung carcinoids.
References
Swarts DRA, Ramaekers FCS, Speel EJM (2012) Molecular and cellular biology of neuroendocrine lung tumors: evidence for separate biological entities. Biochim Biophys Acta 1826:255–271. doi:10.1016/j.bbcan.2012.05.001
Sachithanandan N, Harle RA, Burgess JR (2005) Bronchopulmonary carcinoid in multiple endocrine neoplasia type 1. Cancer 103:509–515. doi:10.1002/cncr.20825
Veschi S, Lattanzio R, Aceto G et al (2012) Alterations of MEN1 and E-cadherin/β-catenin complex in sporadic pulmonary carcinoids. Int J Oncol 41:1221–1228. doi:10.3892/ijo.2012.1563
Swarts DRA, Scarpa A, Corbo V et al (2014) MEN1 gene mutation and reduced expression are associated with poor prognosis in pulmonary carcinoids. J Clin Endocrinol Metab 99:E374–E378. doi:10.1210/jc.2013-2782
Mäki-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 Chromosomes Cancer 52:1141–1149. doi:10.1002/gcc.22109
Scarpa A, Sikora K, Fassan M et al (2013) Molecular typing of lung adenocarcinoma on cytological samples using a multigene next generation sequencing panel. PLoS ONE 8:e80478. doi:10.1371/journal.pone.0080478
Thorvaldsdóttir H, Robinson JT, Mesirov JP (2013) Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform 14:178–192. doi:10.1093/bib/bbs017
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081. doi:10.1038/nprot.2009.86
Wan PT, Garnett MJ, Roe SM et al (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867. doi:10.1016/S0092-8674(04)00215-6
Lin L, Asthana S, Chan E et al (2014) Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer. Proc Natl Acad Sci USA 111:E748–E757. doi:10.1073/pnas.1320956111
Yanagisawa K, Uchida K, Nagatake M et al (2000) Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers. Oncogene 19:2305–2311. doi:10.1038/sj.onc.1203591
Samuels Y, Waldman T (2010) Oncogenic mutations of PIK3CA in human cancers. Curr Top Microbiol Immunol 347:21–41. doi:10.1007/82
Capodanno A, Boldrini L, Alì G et al (2012) Phosphatidylinositol-3-kinase α catalytic subunit gene somatic mutations in bronchopulmonary neuroendocrine tumours. Oncol Rep 28:1559–1566. doi:10.3892/or.2012.2017
Fernandez-Cuesta L, Peifer M, Lu X et al (2014) Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun 5:3518. doi:10.1038/ncomms4518
Bertino EM, Confer PD, Colonna JE et al (2009) Pulmonary neuroendocrine/carcinoid tumors: a review article. Cancer 115:4434–4441. doi:10.1002/cncr.24498
Acknowledgments
The authors thank Tiina Wirtanen for her assistance in sequencing reactions. The study was supported by Sigrid Jusélius Foundation, Cancer Society of Finland, and The Finnish Work Environment Fund.
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical Approval and Informed Consent
All procedures performed in these studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Armengol, G., Sarhadi, V.K., Rönty, M. et al. Driver Gene Mutations of Non-Small-Cell Lung Cancer are Rare in Primary Carcinoids of the Lung: NGS Study by Ion Torrent. Lung 193, 303–308 (2015). https://doi.org/10.1007/s00408-015-9690-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00408-015-9690-1