Minichromosome Maintenance Expression Defines Slow-Growing Gastroenteropancreatic Neuroendocrine Neoplasms

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• 作者：Simon Schimmack^* ; ^&dagger ; ; ^{simon.schimmack@med.uni-heidelberg.de" class="auth_mail" title="E-mail the corresponding author} ; Ben Lawrence^* ; ^{b.lawrence@auckland.ac.nz" class="auth_mail" title="E-mail the corresponding author} ; Barton Kenney^&Dagger ; ; ^{barton.kenney@yale.edu" class="auth_mail" title="E-mail the corresponding author} ; Hubertus Schmitz-Winnenthal^&dagger ; ; ^{winnenthal@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Irvin M. Modlin^* ; ^{imodlin@optonline.net" class="auth_mail" title="E-mail the corresponding author} ; Mark Kidd^* ; ^{mkidd01@snet.net" class="auth_mail" title="E-mail the corresponding author}
• 刊名：Translational Oncology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：9
• 期：5
• 页码：411-418
• 全文大小：1079 K

文摘

BACKGROUND: Small intestinal neuroendocrine neoplasm (SI-NEN) proliferation is quantified by Ki67 measurements which capture G1-G2M phases of the cell cycle. G₀ and early G₁ phases, typical of slow-growing cells, can be detected by minichromosome maintenance protein (MCM) expression. We hypothesized that these replication licensing markers may provide clinically relevant information to augment Ki67 in low-grade neuroendocrine neoplasia. METHODS: Immunohistochemical staining (IHC), Western blot analysis, quantitative polymerase chain reaction, and copy number variations of MCM2, MCM3, and Ki67 were undertaken in SI-NENs (n = 22). MCM and Ki67 expression was compared by Kaplan-Meier survival analysis (tissue microarray, independent set [n = 55]). Forty-three pancreatic NENs and 14 normal tissues were included as controls. RESULTS: In SI-NENs, MCM2 (mean: 21.2%: range: 16%-25%) and MCM3 (28.7%: 22%-34%) were detected in significantly more cells than Ki67 (2.3%: 0%-7%, P < .01). MCM2 mRNA correlated with Ki67 IHC (P < .05). MCM3 protein expression was higher in metastases (38-fold) than in normal small intestine (P = .06) and was largely absent in normal neuroendocrine cells. There was considerable variation at the MCM copy number level (0-4 copies). MCM3 expression in proliferating cells significantly predicted overall survival (P < .002). Combinations of Ki67 and MCM2/3 in algorithms differentiated low and higher proliferative lesions (overall survival: 12 vs 6.1 years, P = .06). MCM expression was not informative in pancreatic NENs. CONCLUSION: MCMs are expressed in a higher proportion of NEN cells than Ki67 in slow-growing small intestinal lesions and correlate with survival. Assessment can be used to augment Ki67 to improve prognostic classification in these low-grade tumors.