BIRC6-ALK, a Novel Fusion Gene in ALK Break-Apart FISH-Negative Lung Adenocarcinoma, Responds to Crizotinib Ling Shan, PhD, Peidi Jiang, MD, Feng Xu,

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BIRC6-ALK, a Novel Fusion Gene in ALK Break-Apart FISH-Negative Lung Adenocarcinoma, Responds to Crizotinib Ling Shan, PhD, Peidi Jiang, MD, Feng Xu, MD, Weilong Zhang, Lei Guo, Jian Wu, MD, PhD, Yixin Zeng, MD, PhD, Yuchen Jiao, MD, PhD, Jianming Ying, MD, PhD Journal of Thoracic Oncology Volume 10, Issue 6, Pages e37-e39 (June 2015) DOI: 10.1097/JTO.0000000000000467 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 A. VENTANA ALK (D5F3) IHC assay revealed intense granular cytoplasmic staining in this case. Original magnification ×200. B, Specimen hybridized with the Vysis break-apart ALK FISH assay showing multiple single 5′ ALK signals (green) with two copies of fused 5′ and 3′ ALK signals (white arrows and a box). C, E, CT scan of mediastinal lymph nodes and thorax before initiation of crizotinib. D, F, CT scan of mediastinal lymph nodes and thorax after 1 month therapy of crizotinib. G, CT scan of thorax after 3-month therapy of crizotinib. IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; CT, computed tomography. Journal of Thoracic Oncology 2015 10, e37-e39DOI: (10.1097/JTO.0000000000000467) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 A, Both the ALK gene and the BIRC6 gene map to chromosome 2p, but have opposite orientations. BIRC6 located at 2.4 Mb downstream of ALK and 9.5 Mb upstream of EML4. Direct Sanger sequencing in this case showed that BIRC6 is disrupted at a position, 7.2 kb downstream of exon 10 and is inverted to connect to a position 411 bp upstream of exon 20 of ALK. Given the short distance (~3 Mb) between 2 breakpoints in ALK and BIRC6, the inversion was not revealed by breaking-apart signals in FISH analysis. B, Fusion of the N-terminal portion of BIRC6 (comprising BIR and UBCc domain) to the intracellular region of ALK (containing the TM and tyrosine kinase domain). BIR, a baculoviral inhibition of apoptosis protein repeat domain; UBCc, a ubiquitin-conjugating enzyme E2, catalytic domain; TM, transmembrane domain. Journal of Thoracic Oncology 2015 10, e37-e39DOI: (10.1097/JTO.0000000000000467) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions