SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy

Xiaolin Ji,Xinyang Li,Mengxue Zhang,Rui Wu,Fang Mei,Buwen Yao,Jiangfeng You,Yan Liu,Fei Pei

doi:10.1038/s41598-021-93484-2

Xiaolin Ji, Xinyang Li + Show 7 more

Open Access

https://doi.org/10.1038/s41598-021-93484-2

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Abstract

The screening of non-small cell lung cancer (NSCLC) tumors for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is important because of the dramatically favorable therapy response to ALK inhibitor. However, the exact mechanism of poor survival in ALK fusion lung cancer patients without receiving targeted therapy is unclear. In this study, total of 521 tumor specimens from Chinese patients with lung cancer were screened for ALK fusion by immunohistochemistry (IHC) and confirmed by fluorescence in situ hybridization (FISH). As results, there were no cases of coexisting EGFR and ALK mutations identified. Fourteen cases (2.7%) harbored ALK fusion, including eight solid adenocarcinomas with signet ring cell features, four acinar adenocarcinomas with cribriform pattern containing mucin, one adenosquamous carcinoma and one micropapillary adenocarcinoma with mucin. Six (42.9%) of fourteen patients with ALK-positive lung cancer had stage IV disease, and five ALK-positive patients treated with platinum-based chemotherapy had poor outcome (all patients were dead and the mean survival time was 12 months), compared to 72 months for patients with ALK inhibitor therapy. Furthermore, Five ALK-positive cases were analyzed by whole exome sequencing (WES) and via direct transcript counting using a digital probe-base (NanoString) to explore the driver genes. Deregulation of PI3K/AKT signaling pathway in ALK-positive lung cancer was demonstrated by WES analysis, and significantly increased mRNA of ALK, ROS1, MET, SPP1 and PI3K signaling pathway was identified by NanoString assay. The concordance between NanoString, IHC and FISH methodologies for detecting ALK fusion was 100%. Significant overexpression of SPP1 protein in ALK-positive lung cancer was confirmed by IHC compared to paired adjacent normal tissues and ALK-negative cancers. Thus we concluded that SPP1 overexpression is associated with poor outcomes for patients with ALK fusion lung cancer without receiving targeted therapy and PI3K/AKT/SPP1 pathway may become the promising targets in patients with aggressive lung cancer.

Highlights

75.3% harbored EGFR mutations, 6% had HER2 mutations, 5% had anaplastic lymphoma kinase (ALK) fusions, 2% had KRAS mutations, and 1% harbored ROS1 fusions
The total of 521 patients with lung cancer were screened for ALK fusion through immunohistochemistry of ALK (ALK IHC), and ALK fluorescence in situ hybridization (FISH) analysis was performed in ALK IHC positive cases
There were no cases of coexisting EGFR and ALK mutations identified

Summary

Introduction

75.3% harbored EGFR mutations, 6% had HER2 mutations, 5% had ALK fusions, 2% had KRAS mutations, and 1% harbored ROS1 fusions These findings suggested that most patients with NSCLC would benefit from targeted therapy. Within these driver oncogenes, the anaplastic lymphoma kinase (ALK) gene rearrangement was identified in NSCLC in 20079. The molecular mechanism of poor outcomes in ALK fusion lung cancer patients who did not receive targeted therapy is unclear. We hypothesized that tumor levels of SPP1 would correlate with poor outcomes in patients with ALK fusion lung cancer who did not receive targeted therapy. We report the frequency of ALK fusion in a cohort of 521 Chinese lung cancer patients, and analyze the presence of ALK fusion in relation to clinicopathological characteristics and other driver genes mutations or expression (including SPP1) using whole exome sequencing (WES) and NanoString-based assay

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