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This article has an addendum. Addendum in: Oncotarget. 2022; 13:1302-1302.

Unravelling actionable biology using transcriptomic data to integrate mitotic index and Ki-67 in the management of lung neuroendocrine tumors

Venkata S.K. Manem, Olga Sazonova, Andréanne Gagné, Michèle Orain, Babak Khoshkrood-Mansoori, Nathalie Gaudreault, Yohan Bossé and Philippe Joubert _

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Oncotarget. 2021; 12:209-220. https://doi.org/10.18632/oncotarget.27874

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Venkata S.K. Manem1, Olga Sazonova1, Andréanne Gagné1, Michèle Orain1, Babak Khoshkrood-Mansoori1, Nathalie Gaudreault1, Yohan Bossé1,2 and Philippe Joubert1,3

1 Quebec Heart and Lung Institute Research Center, Quebec City, QC G1V4G5, Canada

2 Department of Molecular Medicine, Laval University, Quebec City, QC G1V4G5, Canada

3 Department of Medical Biochemistry, Molecular Biology and Pathology, Laval University, Quebec City, QC G1V4G5, Canada

Correspondence to:

Philippe Joubert,email: [email protected]

Keywords: mitotic index; Ki-67; transcriptomics; lung neuroendocrine tumors; pathway analysis

Abbreviations: NET: Neuroendocrine tumors; LCNEC: Large cell neuroendocrine carcinoma; GSEA: Gene set enrichment analysis

Received: December 06, 2020     Accepted: January 19, 2021     Published: February 02, 2021

Copyright: © 2021 Manem et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Pulmonary neuroendocrine tumors (NETs) are a heterogeneous family of malignancies whose classification relies on morphology and mitotic rate, unlike extrapulmonary neuroendocrine tumors that require both mitotic rate and Ki-67. As mitotic count is proportional to Ki-67, it is crucial to understand if Ki-67 can complement the existing diagnostic guidelines, as well as discover the benefit of these two markers to unravel the biological heterogeneity. In this study, we investigated the association of mitotic rate and Ki-67 at gene- and pathway-level using transcriptomic data in lung NET malignancies. Lung resection tumor specimens obtained from 28 patients diagnosed with NETs were selected. Mitotic rate, Ki-67 and transcriptomic data were obtained for all samples. The concordance between mitotic rate and Ki-67 was evaluated at gene-level and pathway-level using gene expression data. Our analysis revealed a strong association between mitotic rate and Ki-67 across all samples and cell cycle genes were found to be differentially ranked between them. Pathway analysis indicated that a greater number of pathways overlapped between these markers. Analyses based on lung NET subtypes revealed that mitotic rate in carcinoids and Ki-67 in large cell neuroendocrine carcinomas provided comprehensive characterization of pathways among these malignancies. Among the two subtypes, we found distinct leading-edge gene sets that drive the enrichment signal of commonly enriched pathways between mitotic index and Ki-67. Overall, our findings delineated the degree of benefit of the two proliferation markers, and offers new layer to predict the biological behavior and identify high-risk patients using a more comprehensive diagnostic workup.

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