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Clinicopathological Features of ALK Expression in 9889 Cases of Non-small-Cell Lung Cancer and Genomic Rearrangements Identified by Capture-Based Next-Generation Sequencing: A Chinese Retrospective Analysis

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Abstract

Background

The clinicopathological features and genomic rearrangements of anaplastic lymphoma kinase (ALK) fusion cases have not been fully identified.

Objective

Our objective was to explore the status of ALK in non-small-cell lung cancer (NSCLC) specimens, to explore the relationships between ALK status and clinicopathological features and to identify genomic rearrangements via capture-based next-generation sequencing (NGS).

Methods

We tested 9889 NSCLC specimens for ALK status using the Ventana anti-ALK (D5F3) antibody. Clinicopathological features were analyzed and genomic rearrangements identified using capture-based NGS in 76 ALK-positive cases.

Results

In total, 485 specimens (4.90%) tested positive for ALK. The positivity rate was higher for adenocarcinoma samples than for non-adenocarcinoma samples (6.03 vs. 1.47%; p < 0.001) and for biopsies/cell blocks than for surgical specimens (7.00 vs. 4.16%; p < 0.001). Patient age, patient sex, specimen type, specimen histotype, and patient smoking history were all significantly correlated with ALK status. Genomic rearrangements were detected in 98.68% (75/76) of the ALK-positive samples; 89.33% (67/75) carried the canonical EML4-ALK, and the remaining samples carried only noncanonical ALK rearrangements. Four of these noncanonical ALK fusion samples were identified as carrying EML4-ALK transcripts at the RNA level. A novel fusion variant, SRD5A2-ALK, was revealed.

Conclusions

Younger patients with NSCLC, especially those aged < 30 years, were more likely to test positive for ALK. Positive ALK test results were more common in patients with invasive mucinous adenocarcinoma and solid-predominant invasive adenocarcinoma than in patients with other histotypes. Samples that carried only noncanonical ALK rearrangements may also have carried the canonical EML4-ALK, which was not detected by capture-based NGS. EML4-ALK transcripts might result from rare splicing mechanisms without genomic rearrangements.

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Authors and Affiliations

  1. Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, No. 241, West Huai Hai Road, Xv Hui District, Shanghai, 200030, China

    Ruiying Zhao, Jie Zhang, Yuchen Han, Jinchen Shao, Lei Zhu, Chan Xiang, Qing Zhang, Haohua Teng, Gang Qin, Lanxiang Zhao, Min Ye, Jikai Zhao & Wenjie Ding

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  1. Ruiying Zhao
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  2. Jie Zhang
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  3. Yuchen Han
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  7. Qing Zhang
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Correspondence to Jie Zhang.

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Funding

This work was funded by the Shanghai Municipal Commission of Health and Family Planning (Grant number 2018ZHYL0213), the Interdisciplinary Program of Shanghai Jiao Tong University (Grant number ZH2018QNA66) and the Shanghai Chest Hospital Projects for Development of Science and Technology (Grant number YZ2015-ZX).

Conflict of Interest

Ruiying Zhao, Jie Zhang, Yuchen Han, Jinchen Shao, Lei Zhu, Chan Xiang, Qing Zhang, Haohua Teng, Gang Qin, Lanxiang Zhao, Min Ye, Jikai Zhao, and Wenjie Ding have no conflicts of interest that are directly relevant to the content of this article.

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Zhao, R., Zhang, J., Han, Y. et al. Clinicopathological Features of ALK Expression in 9889 Cases of Non-small-Cell Lung Cancer and Genomic Rearrangements Identified by Capture-Based Next-Generation Sequencing: A Chinese Retrospective Analysis. Mol Diagn Ther 23, 395–405 (2019). https://doi.org/10.1007/s40291-019-00389-y

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