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BMC Cancer

, 16:603

Translational oncology


BackgroundIdentification 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.

MethodsALK 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.

ResultsALK 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.

ConclusionThe 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.

Electronic supplementary materialThe online version of this article doi:10.1186-s12885-016-2646-x contains supplementary material, which is available to authorized users.

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Autor: Johanna S. M. Mattsson - Hans Brunnström - Verena Jabs - Karolina Edlund - Karin Jirström - Stephanie Mindus - Linnéa 


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