TY - JOUR
T1 - Silencing of UCHL1 by CpG Promoter Hyper-methylation is Associated with Metastatic Gastroenteropancreatic Well-Differentiated Neuroendocrine (Carcinoid) Tumors
AU - Kleiman, David A.
AU - Beninato, Toni
AU - Sultan, Samuel
AU - Crowley, Michael J.P.
AU - Finnerty, Brendan
AU - Kumar, Ritu
AU - Panarelli, Nicole C.
AU - Liu, Yi Fang
AU - Lieberman, Michael D.
AU - Seandel, Marco
AU - Evans, Todd
AU - Elemento, Olivier
AU - Zarnegar, Rasa
AU - Fahey, Thomas J.
N1 - Funding Information:
ACKNOWLEDGMENT This study was funded by a Grant from the Raymond and Beverly Sackler Foundation, Grant TL1RR024998 of the Clinical and Translational Science Center at Weill Cornell Medical College, and by a donation from the Dancers Care Foundation.
Funding Information:
A prospectively maintained tissue bank was reviewed to identify patients who had undergone surgery for a well-differentiated GEP-NET at a single academic tertiary care referral center between May 2002 and December 2012. Two additional tumor samples were obtained from the Cooperative Human Tissue Network, which is funded by the National Cancer Institute. Only well-differentiated NETs arising in the pancreas, stomach, small bowel, colon, or rectum from patients aged 18 years and older were included in this study. Moderately and poorly differentiated NETs, as well as those arising from primary sites other than those listed above, were excluded. Demographic, clinical, and pathological data, including Ki-67 values, were collected for each patient. Particular attention was paid to the presence of regional nodal or distant metastases at the time of surgery.
Publisher Copyright:
© 2014, Society of Surgical Oncology.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1245/s10434-014-3787-2
DO - 10.1245/s10434-014-3787-2
M3 - Article
C2 - 24854489
AN - SCOPUS:84939883075
SN - 1068-9265
VL - 21
SP - 672
EP - 679
JO - Annals of Surgical Oncology
JF - Annals of Surgical Oncology
IS - 4
ER -