Deficiency in expression and epigenetic DNA Methylation of ASS1 gene in nasopharyngeal carcinoma: negative prognostic impact and therapeutic relevance
- 393 Downloads
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.
KeywordsNasopharyngeal carcinoma Transcriptome ASS1 Prognosis Arginine deprivation
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.
- 2.Chan JPB, Kuo TT, et al. Nasopharyngeal carcinoma World Health Organization classification of tumors—pathology and genetics: head and neck tumors. Lyon: IARC Press; 2005. p. 85–97.Google Scholar
- 3.Fang FM, Chien CY, Tsai WL, Chen HC, et al. Quality of life and survival outcome for patients with nasopharyngeal carcinoma receiving three-dimensional conformal radiotherapy vs. Intensity-modulated radiotherapy—a longitudinal study. Int J Radiat Oncol Biol Phys. 2008;72:356–64.PubMedCrossRefGoogle Scholar
- 9.Wee J, Tan EH, Tai BC, Wong HB, et al. Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol. 2005;23:6730–8.PubMedCrossRefGoogle Scholar
- 24.Delage B, Fennell DA, Nicholson L, McNeish I, et al. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int J Cancer J Int du cancer. 2010;126:2762–72.Google Scholar
- 26.Edge SB, Byrd David R., Compton, Carolyn C., Fritz, April G. American Joint Committee on Cancer: AJCC cancer staging manual. (7th ed.). New York, NY, Springer-Verlag, 2010.Google Scholar
- 27.Huang HY, Wu WR, Wang YH, Wang JW, et al. Ass1 as a novel tumor suppressor gene in myxofibrosarcomas: aberrant loss via epigenetic DNA methylation confers aggressive phenotypes, negative prognostic impact, and therapeutic relevance. Clinical Cancer Res: Off J Am Assoc Cancer Res. 2013;19:2861–72.CrossRefGoogle Scholar
- 29.Nicholson LJ, Smith PR, Hiller L, Szlosarek PW, et al. Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum-induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer. International J Cancer J Int du Cancer. 2009;125:1454–63.CrossRefGoogle Scholar