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Case Reports
. 2012 Sep;7(9):e14-6.
doi: 10.1097/JTO.0b013e3182614ab5.

Next-generation sequencing identifies and immunohistochemistry confirms a novel crizotinib-sensitive ALK rearrangement in a patient with metastatic non-small-cell lung cancer

Nir Peled  1 , Gary Palmer, Fred R Hirsch, Murry W Wynes, Maya Ilouze, Marileila Varella-Garcia, Lior Soussan-Gutman, Geoff A Otto, Philip J Stephens, Jeffrey S Ross, Maureen T Cronin, Doron Lipson, Vincent A Miller
Affiliations
Case Reports

Next-generation sequencing identifies and immunohistochemistry confirms a novel crizotinib-sensitive ALK rearrangement in a patient with metastatic non-small-cell lung cancer

Nir Peled et al. J Thorac Oncol. 2012 Sep.
No abstract available

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Conflict of interest statement

Conflict of Interest

NP, MI – nothing to declare.

GAO, GP, VM, DL, PJS, and MTC are employees and equity holders of Foundation Medicine

FRH: Consultant (advisory board) for Pfizer (compensated) and research agreement through University of Colorado with Ventana/Roche.

LSG: Employee of Oncotest-Teva Pharmaceutical Industries, Petach Tikva, Israel

Figures

Figure 1
Figure 1
Panel A Using a manual FISH technique, paraffin sections were hybridized with fluorescent ALK Break-Apart probe (Abbott Molecular). The specimen displayed an atypical pattern of double 3′ALK signals (red) fused with the 5′ALK signal (green), which was classified as negative for ALK gene rearrangement (< 15% of cells with split signals, 3′ ALK and 5′ ALK signals apart by >2 times signal size or single 3′ ALK signal, 50 cells scored) Panels B, C, and D. ALK IHC was performed using a primary antibody (clone D5F3, Cell Signaling Technology, Inc). All paraffin tissue sections were stained with ALK and were reviewed by two pathologists. The tumor cells have predominantly strong staining (3+) in 50% of the tumor cells (lower right). The remaining tumor cells showed (2+) in 30% (lower left) and (1+) in 20% of the tumor cells thus resulting in a histologic (H) score of 230 on a 0–300 scale. The top right is 200X and bottom two panels are 400X.
Figure 2
Figure 2
a) Hypothetical structure of rearrangement in genomic DNA (top) – complex rearrangement placing EML4 exons 1–13 upstream of ALK exons 20–29, separated by small genomic shards; RNA (bottom) – transcription and splicing remove connective region and generate a canonical EML4-ALK fusion transcript; b) Expression of ALK as measured by RNA-seq coverage, dashed line denotes boundary between exons 19 and 20.
Figure 3
Figure 3
Chest (A) and Pelvic (B) PET CT scans before, after 4 weeks and after 4 months of crizotinib.
See this image and copyright information in PMC

References

    1. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–703. - PMC - PubMed
    1. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247–53. - PMC - PubMed
    1. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190–203. - PubMed

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