Abstract
Detection of gene rearrangements has evolved from classical cytogenetic karyotyping through CGH/aCGH to FISH and RT-PCR. Gene rearrangements cause fusion protein overexpression, and immunohistochemistry (IHC) has been increasingly used as a surrogate method for detection of gene rearrangements. Recently several next-generation sequencing platforms for detection of gene fusions have been developed and implemented into clinical practice. Gene rearrangements have been successfully identified with both FISH and IHC in isolated circulating tumor cells (CTCs). CTCs and cell-free tumor DNA (cfDNA) will most likely be used in clinical practice for detection of rearrangements. This chapter will mainly focus on ALK FISH and RT-PCR assays as an example for translocation testing in lung cancer.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. 2013;137(6):828–60.
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–6.
Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S, Inamura K, et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res. 2009;15(9):3143–9.
Togashi Y, Soda M, Sakata S, Sugawara E, Hatano S, Asaka R, et al. KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One. 2012;7(2):e31323.
Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693–703.
Camidge DR, Theodoro M, Maxson DA, Skokan M, O’Brien T, Lu X, et al. Correlations between the percentage of tumor cells showing an anaplastic lymphoma kinase (ALK) gene rearrangement, ALK signal copy number, and response to crizotinib therapy in ALK fluorescence in situ hybridization-positive nonsmall cell lung cancer. Cancer. 2012;118(18):4486–94.
Conde E, Suarez-Gauthier A, Benito A, Garrido P, Garcia-Campelo R, Biscuola M, et al. Accurate identification of ALK positive lung carcinoma patients: novel FDA-cleared automated fluorescence in situ hybridization scanning system and ultrasensitive immunohistochemistry. PLoS One. 2014;9(9):e107200.
Cutz JC, Craddock KJ, Torlakovic E, Brandao G, Carter RF, Bigras G, et al. Canadian anaplastic lymphoma kinase study: a model for multicenter standardization and optimization of ALK testing in lung cancer. J Thorac Oncol. 2014;9(9):1255–63.
Djalalov S, Beca J, Hoch JS, Krahn M, Tsao MS, Cutz JC, et al. Cost effectiveness of EML4-ALK fusion testing and first-line crizotinib treatment for patients with advanced ALK-positive non-small-cell lung cancer. J Clin Oncol. 2014;32(10):1012–9.
Shan L, Jiang P, Xu F, Zhang W, Guo L, Wu J, et al. BIRC6-ALK, a novel fusion gene in ALK break-apart FISH-negative lung adenocarcinoma responds to crizotinib. J Thorac Oncol. 2015;10(6):e37–9.
Li W, Zhang J, Guo L, Chuai S, Shan L, Ying J. Combinational analysis of FISH and immunohistochemistry reveals rare genomic events in ALK fusion patterns in NSCLC that responds to crizotinib treatment. J Thorac Oncol. 2017;12(1):94–101.
Gao X, Sholl LM, Nishino M, Heng JC, Janne PA, Oxnard GR. Clinical implications of variant ALK FISH rearrangement patterns. J Thorac Oncol. 2015;10(11):1648–52.
Dacic S, Villaruz LC, Abberbock S, Mahaffey A, Incharoen P, Nikiforova MN. ALK FISH patterns and the detection of ALK fusions by next generation sequencing in lung adenocarcinoma. Oncotarget. 2016;7(50):82943–52.
Takeuchi K, Togashi Y, Kamihara Y, Fukuyama T, Yoshioka H, Inoue A, et al. Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study). Ann Oncol. 2016;27(1):185–92.
Lira ME, Kim TM, Huang D, Deng S, Koh Y, Jang B, et al. Multiplexed gene expression and fusion transcript analysis to detect ALK fusions in lung cancer. J Mol Diagn. 2013;15(1):51–61.
McLeer-Florin A, Moro-Sibilot D, Melis A, Salameire D, Lefebvre C, Ceccaldi F, et al. Dual IHC and FISH testing for ALK gene rearrangement in lung adenocarcinomas in a routine practice: a French study. J Thorac Oncol. 2012;7(2):348–54.
Pekar-Zlotin M, Hirsch FR, Soussan-Gutman L, Ilouze M, Dvir A, Boyle T, et al. Fluorescence in situ hybridization, immunohistochemistry, and next-generation sequencing for detection of EML4-ALK rearrangement in lung cancer. Oncologist. 2015;20(3):316–22.
Peled N, Palmer G, Hirsch FR, Wynes MW, Ilouze M, Varella-Garcia M, et al. Next-generation sequencing identifies and immunohistochemistry confirms a novel crizotinib-sensitive ALK rearrangement in a patient with metastatic non-small-cell lung cancer. J Thorac Oncol. 2012;7(9):e14–6.
Sholl LM, Weremowicz S, Gray SW, Wong KK, Chirieac LR, Lindeman NI, et al. Combined use of ALK immunohistochemistry and FISH for optimal detection of ALK-rearranged lung adenocarcinomas. J Thorac Oncol. 2013;8(3):322–8.
Weickhardt AJ, Aisner DL, Franklin WA, Varella-Garcia M, Doebele RC, Camidge DR. Diagnostic assays for identification of anaplastic lymphoma kinase-positive non-small cell lung cancer. Cancer. 2013;119(8):1467–77.
Ali SM, Hensing T, Schrock AB, Allen J, Sanford E, Gowen K, et al. Comprehensive genomic profiling identifies a subset of crizotinib-responsive ALK-rearranged non-small cell lung cancer not detected by fluorescence in situ hybridization. Oncologist. 2016;21(6):762–70.
Jang JS, Wang X, Vedell PT, Wen J, Zhang J, Ellison DW, et al. Custom gene capture and next-generation sequencing to resolve discordant ALK status by FISH and IHC in lung adenocarcinoma. J Thorac Oncol. 2016;11(11):1891–900.
Wiesner T, Lee W, Obenauf AC, Ran L, Murali R, Zhang QF, et al. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature. 2015;526(7573):453–7.
Soda M, Isobe K, Inoue A, Maemondo M, Oizumi S, Fujita Y, et al. A prospective PCR-based screening for the EML4-ALK oncogene in non-small cell lung cancer. Clin Cancer Res. 2012;18(20):5682–9.
Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S, et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res. 2008;68(13):4971–6.
Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18(3):378–81.
Rimkunas VM, Crosby KE, Li D, Hu Y, Kelly ME, Gu TL, et al. Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: identification of a FIG-ROS1 fusion. Clin Cancer Res. 2012;18(16):4449–57.
Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30(8):863–70.
Tsuta K, Kohno T, Yoshida A, Shimada Y, Asamura H, Furuta K, et al. RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis. Br J Cancer. 2014;110(6):1571–8.
Sasaki H, Shimizu S, Tani Y, Maekawa M, Okuda K, Yokota K, et al. RET expression and detection of KIF5B/RET gene rearrangements in Japanese lung cancer. Cancer Med. 2012;1(1):68–75.
Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18(3):375–7.
Dacic S, Luvison A, Evdokimova V, Kelly L, Siegfried JM, Villaruz LC, et al. RET rearrangements in lung adenocarcinoma and radiation. J Thorac Oncol. 2014;9(1):118–20.
Wang R, Hu H, Pan Y, Li Y, Ye T, Li C, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30(35):4352–9.
Kohno T, Nakaoku T, Tsuta K, Tsuchihara K, Matsumoto S, Yoh K, et al. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl Lung Cancer Res. 2015;4(2):156–64.
Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19(11):1469–72.
Fernandez-Cuesta L, Plenker D, Osada H, Sun R, Menon R, Leenders F, et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov. 2014;4(4):415–22.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this chapter
Cite this chapter
Dacic, S. (2018). Translocation Testing of Lung Cancer Biomarkers. In: Cagle, P., et al. Precision Molecular Pathology of Lung Cancer. Molecular Pathology Library. Springer, Cham. https://doi.org/10.1007/978-3-319-62941-4_8
Download citation
DOI: https://doi.org/10.1007/978-3-319-62941-4_8
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-62940-7
Online ISBN: 978-3-319-62941-4
eBook Packages: MedicineMedicine (R0)