Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer

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Abstract

Background: Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data. Methods: ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients. Results: ALK rearrangements were detected in 1.7 % in the complete cohort and 2.0 % in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.8 and 1.4 % when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (>98 %), while the sensitivity was between 69 % (Ventana) and 62 % (in house Dako protocol). Furthermore, only 67 % of the ALK IHC positive cases were positive with both IHC assays. Gene expression analysis revealed that 6/194 (3 %) tumors showed high ALK gene expression (≥6 AU) and of them only three were positive by either FISH or IHC. Conclusion: The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC.

Detaljer

Författare
  • Johanna S M Mattsson
  • Hans Brunnström
  • Verena Jabs
  • Karolina Edlund
  • Karin Jirström
  • Stephanie Mindus
  • Linnéa la Fleur
  • Fredrik Pontén
  • Mats G. Karlsson
  • Christina Karlsson
  • Hirsh Koyi
  • Eva Brandén
  • Johan Botling
  • Gisela Helenius
  • Patrick Micke
  • Maria A. Svensson
Enheter & grupper
Externa organisationer
  • Uppsala universitet
  • Skåne University Hospital
  • Technical University of Dortmund
  • Örebro University
  • Gävle Hospital
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Artikelnummer603
TidskriftBMC Cancer
Volym16
Utgåva nummer1
StatusPublished - 2016 aug 5
PublikationskategoriForskning
Peer review utfördJa