Silencing of UCHL1 by CpG promoter hyper-methylation is associated with metastatic gastroenteropancreatic well-differentiated neuroendocrine (carcinoid) tumors.

TitleSilencing of UCHL1 by CpG promoter hyper-methylation is associated with metastatic gastroenteropancreatic well-differentiated neuroendocrine (carcinoid) tumors.
Publication TypeJournal Article
Year of Publication2014
AuthorsKleiman DA, Beninato T, Sultan S, Crowley MJP, Finnerty B, Kumar R, Panarelli NC, Liu Y-F, Lieberman MD, Seandel M, Evans T, Elemento O, Zarnegar R, Fahey TJ
JournalAnn Surg Oncol
Volume21 Suppl 4
Date Published2014 Dec
KeywordsAdult, Aged, Blood Vessels, Carcinoid Tumor, CpG Islands, Digestive System Neoplasms, Female, Gene Silencing, Humans, Ki-67 Antigen, Male, Methylation, Middle Aged, Mitotic Index, Neoplasm Invasiveness, Neoplasm Metastasis, Promoter Regions, Genetic, Risk Factors, Sensitivity and Specificity, Ubiquitin Thiolesterase

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

Alternate JournalAnn. Surg. Oncol.
PubMed ID24854489
PubMed Central IDPMC4378537
Grant ListTL1 RR024998 / RR / NCRR NIH HHS / United States
TL1RR024998 / RR / NCRR NIH HHS / United States