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Tumor Biology

, Volume 35, Issue 1, pp 161–169 | Cite as

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

  • Jui Lan
  • Hui-Chun Tai
  • Sung-Wei Lee
  • Tzu-Ju Chen
  • Hsuan-Ying Huang
  • Chien-Feng Li
Research Article

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.

Keywords

Nasopharyngeal carcinoma Transcriptome ASS1 Prognosis Arginine deprivation 

Notes

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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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Jui Lan
    • 1
  • Hui-Chun Tai
    • 2
  • Sung-Wei Lee
    • 3
  • Tzu-Ju Chen
    • 4
  • Hsuan-Ying Huang
    • 1
  • Chien-Feng Li
    • 4
    • 5
    • 6
    • 7
    • 8
  1. 1.Departments of PathologyKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
  2. 2.Department of PathologyChanghua Christian HospitalChanghuaTaiwan
  3. 3.Department of Radiation OncologyChi-Mei Medical CenterTainanTaiwan
  4. 4.Department of PathologyChi-Mei Medical CenterTainanTaiwan
  5. 5.National Institute of Cancer Research, National Health Research InstitutesTainanTaiwan
  6. 6.Department of BiotechnologySouthern Taiwan University of Science and TechnologyTainanTaiwan
  7. 7.Department of PathologyKaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiungTaiwan
  8. 8.Institute of Clinical MedicineKaohsiung Medical UniversityKaohsiungTaiwan

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