Silencing of UCHL1 by CpG promoter hyper-methylation is associated with metastatic gastroenteropancreatic well-differentiated neuroendocrine (carcinoid) tumors.
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.
Division of Endocrine and Minimally Invasive Surgery, Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA.
David A
DA
Kleiman
Toni
T
Beninato
Samuel
S
Sultan
Michael J P
MJ
Crowley
Brendan
B
Finnerty
Ritu
R
Kumar
Nicole C
NC
Panarelli
Yi-Fang
YF
Liu
Michael D
MD
Lieberman
Marco
M
Seandel
Todd
T
Evans
Olivier
O
Elemento
Rasa
R
Zarnegar
Thomas J
TJ
Fahey
D000328:Adult; D000368:Aged; D001808:Blood Vessels / Q000473:pathology; D002276:Carcinoid Tumor / Q000737:chemistry / Q000235:genetics* / Q000556:secondary*; D018899:CpG Islands / Q000235:genetics*; D004067:Digestive System Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008745:Methylation; D008875:Middle Aged; D008940:Mitotic Index; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D012680:Sensitivity and Specificity; D043222:Ubiquitin Thiolesterase / Q000032:analysis / Q000235:genetics*
D019394:Ki-67 Antigen; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase