Immense random colocalization, revealed by automated high content image cytometry, seriously questions FISH as gold standard for detecting EML4-ALK fusion

Cytometry. Part a : the Journal of the International Society for Analytical Cytology
Gábor SmukGábor Pajor

Abstract

EML4-ALK gene fusion (inv2(p21p23)) of non-small cell lung cancer (NSCLC) predisposes to tyrosine kinase inhibitor treatment. One of the gold standard diagnostics is the dual color (DC) break-apart (BA) FISH technique, however, the unusual closeness of the involved genes has been suggested to raise likelihood of random co-localization (RCL) of signals. Although this is suspected to decrease sensitivity (often to as low as 40-70%), the exact level and effect of RCL has not been revealed thus far. Signal distances were analyzed to the 0.1 µm precision in more than 25,000 nuclei, via automated high content-image cytometry. Negative and positive controls were created using conventional DC BA-, and inv2(p21p23) mimicking probe-sets, respectively. Average distance between red and green signals was 9.72 pixels (px) (±5.14px) and 3.28px (±2.44px), in positives and negatives, respectively; overlap in distribution being 41%. Specificity and sensitivity of correctly determining ALK status was 97% and 29%, respectively. When investigating inv2(p21p23) with DC BA FISH, specificity is high, but seven out of ten aberrant nuclei are inevitably falsely classified as negative, due to the extreme level of RCL. Together with genetic heterogeneity ...Continue Reading

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Citations

Aug 30, 2018·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Arnaud Uguen
Jun 14, 2019·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Julia A BridgeAndrew S Brohl
Apr 23, 2019·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Hans Minderman

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