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Deficiency in expression and epigenetic DNA Methylation of ASS1 gene in nasopharyngeal carcinoma: negative prognostic impact and therapeutic relevance

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Tumor Biology

Abstract

The risk stratification and final outcomes in patients with nasopharyngeal carcinomas (NPC) still remain suboptimal. Our principal goals were to identify and validate targetable metabolic drivers relevant to pathogenesis of NPC using a published transcriptome. One prominently downregulated gene regulating amino acid metabolism was found to be argininosuccinate synthetase (ASS1). Attributable to epigenetic DNA methylation, ASS1 deficiency may link to the therapeutic sensitivity to the arginine-depriving agents and promote tumor aggressiveness through its newly identified tumor suppressor function. ASS1 immunohistochemistry was therefore examined in a well-defined cohort of 124 NPC biopsy specimens and in the neck lymph node metastases of another ten independent cases. For the latter, bisulphite pyrosequencing was performed to evaluate the extent of ASS1 gene methylation. ASS1 protein deficiency was identified in 64 of 124 cases (51.6 %), significantly related to T3–T4 status (p = 0.006), and univariately associated with inferior local recurrence-free survival (p = 0.0427), distant metastasis-free survival (DMFS; p = 0.0036), and disease-specific survival (DSS; p = 0.0069). Together with advanced AJCC stages III–IV, ASS1 protein deficiency was also independently predictive of worse outcomes for the DFMS (p = 0.010, hazard ratio = 2.241) and DSS (p = 0.020, hazard ratio = 1.900). ASS1 promoter hypermethylation was detected in eight of ten neck nodal metastatic lesions by bisulphite pyrosequencing and associated with ASS1 protein deficiency (p < 0.001). In summary, ASS1 protein deficiency was seen in approximately a half of NPCs and associated with advanced T classification, DNA methylation, and clinical aggressiveness, consistent with its tumor suppressor role. This aberration may render pegylated arginine deiminase as a promising strategy for ASS1-deficient NPCs.

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Acknowledgments

The authors thank the Chang Gung genomic core laboratory for technical assistance (CMRPG880251).This work was sponsored by Chi-Mei Medical Center (to C.-F. Li).

Conflicts of interest

No conflicts of interest were declared.

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Authors and Affiliations

  1. Departments of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Jui Lan & Hsuan-Ying Huang

  2. Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan

    Hui-Chun Tai

  3. Department of Radiation Oncology, Chi-Mei Medical Center, Liouying, Tainan, Taiwan

    Sung-Wei Lee

  4. Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan

    Tzu-Ju Chen & Chien-Feng Li

  5. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

    Chien-Feng Li

  6. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan

    Chien-Feng Li

  7. Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Chien-Feng Li

  8. Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Chien-Feng Li

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  1. Jui Lan
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  2. Hui-Chun Tai
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  6. Chien-Feng Li
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Correspondence to Chien-Feng Li.

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Authors’ contributions

Conception and design: C.-F. Li, J Lan, H.-Y. Huang

Development of methodology: C.-F. Li, H-Y. Huang

Acquisition of data: S.-W. Lee, T.-J. Chen, H.-C. Tai

Analysis and interpretation of data: C.-F. Li, J. Lan,

Writing and/or revision of the manuscript: C.-F. Li, J. Lan

Study supervision: C.-F. Li

All authors read and approved the final manuscript

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Lan, J., Tai, HC., Lee, SW. et al. Deficiency in expression and epigenetic DNA Methylation of ASS1 gene in nasopharyngeal carcinoma: negative prognostic impact and therapeutic relevance. Tumor Biol. 35, 161–169 (2014). https://doi.org/10.1007/s13277-013-1020-8

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  • DOI: https://doi.org/10.1007/s13277-013-1020-8

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