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SHP-1 promoter 2 methylation in cerebrospinal fluid for diagnosis of leptomeningeal epithelial-derived malignancy (carcinomatous meningitis)

  • Laboratory Investigation
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Abstract

Current diagnostic methods for leptomeningeal metastasis (LM) from epithelial-derived malignancy (EDM) have limited sensitivity. Here, we explored SHP-1 promoter 2 methylation (SHP1P2)—an epithelial-specific methylation marker previously proven as risk stratification and potential diagnostic marker in non-small cell lung cancer—for EDM with LM. We prospectively recruited 136 patients who were diagnosed EDM with LM (n = 25), EDM without LM (n = 14), non-EDM with LM (n = 8), and benign meningeal diseases (n = 89). The primary cancer sites for EDM with LM were lung (n = 17), breast (n = 5), and colon (n = 3). We performed quantitative analyses of cell-free (cfSHP1P2) and whole fraction (wSHP1P2) from cerebrospinal fluid (CSF); results were correlated with the clinicopathological data, including CSF cytology. Median cfSHP1P2 and wSHP1P2 were 3.08 [range: 0–163.5] and 9.35 [0.69–91.63] ng/ml, respectively, in EDM with LM; 0 [0–0.08] and 0.23 [0–7.84] ng/ml in EDM without LM; and were undetectable in most cases of benign meningeal diseases and non-EDM with LM. The cut-off values of 0.22 ng/ml for methylated cfSHP1P2 and 0.59 ng/ml for wSHP1P2 were the best to discriminate EDM with LM from EDM without LM (sensitivity: 79–100 %; specificity: 83–100 %), as well as from other benign conditions (sensitivity: 85–100 % specificity: 78–100 %). CSF cytology yielded 76 % sensitivity for diagnosing EDM with LM. Further validation of CSF SHP1P2 methylation detection as a role of adjunctive tool for LM from EDM should be interested based on our study.

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Acknowledgments

This project was financially supported by the Ratchadaphiseksomphot Endowment Fund (RA48/56), Faculty of Medicine, Chulalongkorn University (to CV), and CU Research Cluster: 2014 Ratchadaphiseksomphot Endowment Fund, Chulalongkorn University (CU-57-001-HR) (to VS).

Authors’ contributions

CV had substantial contributions to study design, data acquisition and analysis and draft the manuscript, SM participated in data acquisition, NJ contributed imaging review, IT participated in study design and draft the manuscript, VS participated to conceive the study, AM participated to conceive the study, participated in study design, SS participated to conceive the study, participated in study design and had given final approval of the version to be published. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Medicine, Faculty of Medicine, Chulalongkorn University and the King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand

    Chanida Vinayanuwattikun, Siyamol Mingmalairak, Iyavut Thaipisuttikul & Virote Sriuranpong

  2. Department of Radiology, Faculty of Medicine, Chulalongkorn University and the King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand

    Nutchawan Jittapiromsak

  3. Department of Anatomy and Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Faculty of Medicine, Chulalongkorn University and the King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand

    Apiwat Mutirangura

  4. Department of Pathology and Chulalongkorn GenePRO Center, Faculty of Medicine, Chulalongkorn University and the King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand

    Shanop Shuangshoti

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  1. Chanida Vinayanuwattikun
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  2. Siyamol Mingmalairak
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Correspondence to Shanop Shuangshoti.

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Vinayanuwattikun, C., Mingmalairak, S., Jittapiromsak, N. et al. SHP-1 promoter 2 methylation in cerebrospinal fluid for diagnosis of leptomeningeal epithelial-derived malignancy (carcinomatous meningitis). J Neurooncol 129, 395–403 (2016). https://doi.org/10.1007/s11060-016-2199-5

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