A rational diagnostic algorithm for the identification of ALK rearrangement in lung cancer: a comprehensive study of surgically treated Japanese patients.
BACKGROUND
EML4-ALK fusion gene is found in only a small subset (2-6%) of non-small cell lung cancer. There is an urgent need to establish a rational diagnostic algorithm to identify this rare but important fusion in lung cancer.


METHODS
We performed a comprehensive analysis of EGFR/KRAS mutation and ALK rearrangement in a total of 360 surgically resected lung cancers. ALK rearrangement was examined by 3 analyses: multiplex reverse transcription-PCR, fluorescent in situ hybridization (FISH), and immunohistochemistry (IHC) with the intercalated antibody-enhanced polymer method. A scoring system was used for IHC (iScore). A test set (202 patients with unselected lung cancer) was used for proposing a diagnostic algorithm. This diagnostic algorithm was validated in 158 patients with EGFR and KRAS mutation-negative adenocarcinoma.


RESULTS
ALK rearrangement was identified in 2 patients (1.0%) from the test set and both adenocarcinomas were negative for EGFR and KRAS mutations. The results of FISH and RT-PCR were completely matched. The highest iScore 3 was found only in the 2 positive cases. A diagnostic algorithm was proposed: IHC screening for ALK rearrangement followed by confirmatory FISH. In the validation set, 8 cases (5.1%) had iScore 3 and were positive for FISH, while the other cases had iScore 0 and were negative for FISH.


CONCLUSIONS
Screening for ALK rearrangement by IHC followed by confirmatory FISH is a rational diagnostic algorithm. If needed, patients may be selected for screening ALK rearrangement by their EGFR and KRAS mutation status.
Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
Kazuya
K
Takamochi
Kengo
K
Takeuchi
Takuo
T
Hayashi
Shiaki
S
Oh
Kenji
K
Suzuki
D000328:Adult; D000465:Algorithms; D000077548:Anaplastic Lymphoma Kinase; D044466:Asian People; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D008297:Male; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012680:Sensitivity and Specificity
C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases