Homogeneity and High Concordance of ALK Translocation in Primary Lung Adenocarcinoma and Paired Lymph Node Metastasis

Wei Ma,Jianming Ying,Xiuyun Liu,Lei Guo,Ling Shan,Ning Lyu

doi:10.1038/s41598-017-11453-0

Abstract

Translocation of anaplastic lymphoma kinase (ALK) gene is an important determinator for the response to ALK tyrosine kinase inhibitor (TKI) in non-small-cell lung cancer (NSCLC) patients. The existence of genetic heterogeneity will affect the results of molecular testing, especially in biopsy samples from primary or metastatic sites of patients with advanced stage NSCLC. We intended to explore the heterogeneity of ALK gene translocation in excision specimens and to examine the existence of discordance of ALK status between primary tumours and corresponding lymph node metastases. A total of 106 ALK positive lung adenocarcinoma cases were collected for assessment of intratumour heterogeneity of ALK gene translocation, which were stained by the fully automated Ventana ALK D5F3 immunohistochemistry (IHC) analysis. In addition, the ALK gene translocations were evaluated in a series of 53 primary tumours and their paired lymph node metastases using ALK D5F3 IHC staining. The concordance rate between primary tumours and paired metastatic lymph nodes was 100%. ALK status was homogeneous in lung adenocarcinoma samples and was generally stable during metastasis. Therefore, ALK gene translocation can be measured reliably in material from either primary or metastatic tumours in lung adenocarcinoma patients.

Highlights

Lung cancer causes the largest number of cancer related deaths worldwide
We evaluated the intratumour heterogeneity of anaplastic lymphoma kinase (ALK) gene translocation in 106 ALK-positive excision specimens by the Ventana ALK D5F3 IHC and investigated whether the ALK status changed during disease progression in 53 pairs of primary tumours and corresponding lymph node metastases
We found the ALK expression was homogenous in lung adenocarcinoma samples and there was no discordant case of ALK status between primary tumours and corresponding lymph node metastases

Summary

Introduction

Lung cancer causes the largest number of cancer related deaths worldwide. Currently, more than 85% of lung cancer cases are classified as non-small-cell-lung cancer (NSCLC). Drugs targeting epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations have been successfully used in clinical medicine[2, 3]. ALK gene translocation was first discovered in NSCLC in 20074. The identification of ALK gene translocation in NSCLC is the basis of targeted therapy with ALK inhibitors. IHC analysis showed that EGFR expression in primary NSCLC tumour/metastasis had a discordance rate of 33.3%10. We applied Ventana ALK D5F3 IHC to investigate the heterogeneity of ALK gene translocations in excision specimens and compared the ALK status between primary tumours and their corresponding metastatic lymph nodes. Several recent reports have identified an overlap between ALK translocation and other driver gene www.nature.com/scientificreports/. We analyze the association of ALK gene translocation with the occurrence of other driver gene mutations by directly sequencing the EGFR, KRAS, BRAF, and HER2 gene mutations and with clinicopathological characteristics

Methods

Results

Discussion

Conclusion