Increased ALK Gene Copy Number and Amplification are Frequent in Non-small Cell Lung Cancer

Abstract

Introduction Translocation of the anaplastic lymphoma kinase (ALK) gene is involved in the tumorigenesis of a subset of non-small cell lung carcinomas (NSCLCs) and identifies patients sensitive to ALK inhibitors. ALK copy number changes and amplification, which plays an oncogenic role in tumors such as neuroblastoma, are poorly characterized in NSCLC. We aimed to study the prevalence of ALK copy number changes and their correlation to ALK protein expression, epidermal growth factor receptor (EGFR) status, and clinicopathological data in patients with NSCLC. Methods ALK status was evaluated by fluorescence in situ hybridization (FISH). Specimens with ALK translocation were studied for echinoderm microtubule-associated protein-like 4 (EML4), KIF5B, and TFG status. ALK expression was assessed by immunohistochemistry. EGFR gene and protein status were evaluated in adenocarcinomas. Survival analysis was performed. Results One hundred seven NSCLC cases were evaluated. There were two cases of EML4-ALK translocation and one with an atypical translocation of ALK. Both cases of EML4-ALK translocation had ALK protein expression, whereas in the rest, ALK was undetected. Eleven cases (10%) exhibited ALK amplification and 68 (63%) copy number gains. There was an association between ALK amplification and EGFR FISH positivity (p < 0.0001) but not with prognosis. In conclusion, EML4-ALK translocation is a rare event in NSCLC. Conclusion The study reveals a significant frequency of ALK amplification and its association with EGFR FISH positivity in lung adenocarcinomas. Based on these findings, a potential role of ALK amplification in the response to ALK inhibitors alone or combined with EGFR inhibitors in NSCLC merits further studies.

Targeting Oncogenic ALK: A Promising Strategy for Cancer Treatment

“…In addition, we and others (43,44) have described ALK gene amplification in non-small cell lung cancer (NSCLC) specimens. Our study showed a relatively high frequency of copy number of mainly low level gains (60%), and amplification (10%).…”

Actualización de las recomendaciones para la determinación de biomarcadores en el carcinoma de pulmón avanzado de célula no pequeña. Consenso Nacional de la Sociedad Española de Anatomía Patológica y de la Sociedad Española de Oncología Médica

“…En este sentido es interesante resaltar que un escáner de FISH ha recibido recientemente aprobación por la FDA para la interpretación de la sonda de ALK mencionada anteriormente 23 . Por otro lado, existen alteraciones en el número de copias del gen ALK que no parecen relacionadas con la buena respuesta al fármaco específico, si bien es preciso estudiar en profundidad los casos con un incremento en el número de copias para no perder posibles casos de presentación atípica 24,25 . La aparición de clones con una sensibilidad apropiada para su uso mediante inmunohistoquímica, como los D5F3 y 5A4, y el uso de técnicas de amplificación para intensificar la señal inmunohistoquímica a base de polímeros, ha provocado que se proponga su uso como método de cribado previo a la confirmación con el método FISH 19,26 .…”

Precision Medicine for Lung Cancer: Role of the Surgical Pathologist

“…In multiple reports, ALK rearrangements are also associated with specific adenocarcinoma subtypes and variant features, most often solid adenocarcinoma pattern with signet ring features. [23][24][25][26][27][28][29] Yoshida et al 28 found that the most powerful histologic indicator of ALK rearrangement by multivariate analysis was the presence of solid signet-ring cell pattern and a mucinous cribriform pattern, which they found to be at least focally present in 78% of ALK þ tumors and only 1% of ALK À tumors. However, the use of histologic subtypes and variants is not currently considered sufficient to select patients for ALK testing because a substantial number of patients who might benefit from treatment but whose tumors lack these features would once again be excluded.…”