Silencing of UCHL1 by CpG Promoter Hyper-methylation is Associated with Metastatic Gastroenteropancreatic Well-Differentiated Neuroendocrine (Carcinoid) Tumors
Well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare tumors with varying metastatic potential. The underlying molecular basis for metastasis by GEP-NETs remains undefined.
Quantitative PCR and immunohistochemistry (IHC) staining for ubiquitin carboxyl-terminal esterase L1 (UCHL1) gene and protein expression was performed on a group of localized and metastatic well-differentiated GEP-NET samples acquired from a prospectively maintained tissue bank. The ability of extent of UCHL1 IHC staining to differentiate localized and metastatic tumors was compared with Ki-67 index.
Among 46 total samples, UCHL1 expression at both the gene and protein level was significantly greater among localized GEP-NETs compared with metastatic tumors and metastases (p < 0.001). Hypermethylation of the UCHL1 promoter was commonly observed among metastatic primary tumors and metastases (those with the lowest UCHL1 expression) but not among localized tumors (p < 0.001). Poor staining (<50 %) for UCHL1 was observed in 27 % of localized tumors compared with 87 % of metastatic tumors (p = 0.001). The presence of <50 % staining for UCHL1 was 88 % sensitive and 73 % specific for identifying metastatic disease. In contrast, there was no association between Ki-67 index and metastatic disease. In multivariable analysis, only UCHL1 staining <50 % [odds ratio (OR) 24.5, p = 0.035] and vascular invasion (OR 38.4, p = 0.03) were independent risk factors for metastatic disease at the time of initial surgery.
Loss of UCHL1 expression by CpG promoter hypermethylation is associated with metastatic GEP-NETs. Extent of UCHL1 staining should be explored as a potentially clinically useful adjunct to Ki-67 index in evaluating GEP-NETs for aggressive features.
- 3.Bosman FT, World Health Organization, International Agency for Research on Cancer. WHO classification of tumours of the digestive system. 2010; International Agency for Research on Cancer: Lyon.Google Scholar
- 4.Ellison TA, Wolfgang CL, Shi C, et al. A single institution’s 26-year experience with nonfunctional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram. Ann Surg. 2014;259(2):204–12.Google Scholar
- 8.Wang YH, Lin Y, Xue L, Wang JH, Chen MH, Chen J. Relationship between clinical characteristics and survival of gastroenteropancreatic neuroendocrine neoplasms: a single-institution analysis (1995–2012) in South China. BMC Endocr Disord. 2012;12:30. doi:10.1186/1472-6823-12-30.PubMedCentralPubMedCrossRefGoogle Scholar
- 26.Yamaguchi T, Fujimori T, Tomita S, et al. Clinical validation of the gastrointestinal NET grading system: Ki67 index criteria of the WHO 2010 classification is appropriate to predict metastasis or recurrence. Diagn Pathol. 2013;8:65. doi:10.1186/1746-1596-8-65.PubMedCentralPubMedCrossRefGoogle Scholar