Spindle assembly checkpoint MAD2 and CDC20 overexpressions and cell-in-cell formation in gastric cancer and its precursor lesions

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Abstract

Overexpression of mitotic arrest deficient 2 (MAD2) and/or cell division cycle 20 (CDC20) in the spindle assembly checkpoint leads to chromosomal instability and aneuploidy. Cell-in-cell (CIC) structures are formed by the process where cancer or immune cells are internalized into adjacent host cancer cells. Here, we investigated the clinicopathological significances of spindle assembly checkpoint protein overexpression and CIC structures in 829 cases of normal, premalignant, and gastric cancer (GC) lesions. MAD2 and CDC20 expressions were significantly increased in intestinal metaplasia, low-grade dysplasia, high-grade dysplasia (HGD), and early GC than normal mucosa, and their expression levels were the highest in HGD. Interestingly, CDC20 immunohistochemistry specifically stained the outer cells of CIC structures, which were the most frequently observed in early GC. In univariate analyses, MAD2 and CDC20 overexpressions and CIC formation were associated with older age, intestinal histology, lower tumor-node-metastasis stage, and longer recurrence-free survival and cancer-specific survival of GC patients. In multivariate survival analyses, MAD2 and CDC20 overexpressions were associated with better recurrence-free survival (hazard ratio, 0.61; P = .012) and cancer-specific survival (hazard ratio, 0.63; P = .043), respectively. In conclusion, MAD2 and CDC20 are the most expressed in HGD, suggesting their roles in the early stage of gastric carcinogenesis, whereas their overexpressions in GC are associated with intestinal histology and favorable clinicopathological parameters, which may be useful for immunohistochemical classification of chromosomal instability–type GC. Moreover, CDC20 is a novel immunohistochemical marker for highlighting CIC structures.

Original languageEnglish
Pages (from-to)174-183
Number of pages10
JournalHuman Pathology
Volume85
DOIs
Publication statusPublished - 2019 Mar 1

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Cell-in-Cell Formation
M Phase Cell Cycle Checkpoints
Stomach Neoplasms
Cell Cycle
Survival
Neoplasms
Histology
Recurrence
Chromosomal Instability
Metaplasia
Aneuploidy
Survival Analysis

Keywords

  • Aneuploidy
  • CDC20
  • Cell-in-cell structure
  • Gastric cancer
  • MAD2

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

@article{497c8c31acb94f5b8eee44c0e8360956,
title = "Spindle assembly checkpoint MAD2 and CDC20 overexpressions and cell-in-cell formation in gastric cancer and its precursor lesions",
abstract = "Overexpression of mitotic arrest deficient 2 (MAD2) and/or cell division cycle 20 (CDC20) in the spindle assembly checkpoint leads to chromosomal instability and aneuploidy. Cell-in-cell (CIC) structures are formed by the process where cancer or immune cells are internalized into adjacent host cancer cells. Here, we investigated the clinicopathological significances of spindle assembly checkpoint protein overexpression and CIC structures in 829 cases of normal, premalignant, and gastric cancer (GC) lesions. MAD2 and CDC20 expressions were significantly increased in intestinal metaplasia, low-grade dysplasia, high-grade dysplasia (HGD), and early GC than normal mucosa, and their expression levels were the highest in HGD. Interestingly, CDC20 immunohistochemistry specifically stained the outer cells of CIC structures, which were the most frequently observed in early GC. In univariate analyses, MAD2 and CDC20 overexpressions and CIC formation were associated with older age, intestinal histology, lower tumor-node-metastasis stage, and longer recurrence-free survival and cancer-specific survival of GC patients. In multivariate survival analyses, MAD2 and CDC20 overexpressions were associated with better recurrence-free survival (hazard ratio, 0.61; P = .012) and cancer-specific survival (hazard ratio, 0.63; P = .043), respectively. In conclusion, MAD2 and CDC20 are the most expressed in HGD, suggesting their roles in the early stage of gastric carcinogenesis, whereas their overexpressions in GC are associated with intestinal histology and favorable clinicopathological parameters, which may be useful for immunohistochemical classification of chromosomal instability–type GC. Moreover, CDC20 is a novel immunohistochemical marker for highlighting CIC structures.",
keywords = "Aneuploidy, CDC20, Cell-in-cell structure, Gastric cancer, MAD2",
author = "Younghye Kim and Jung-Woo Choi and Ju-Han Lee and Kim, {Young Sik}",
year = "2019",
month = "3",
day = "1",
doi = "10.1016/j.humpath.2018.10.029",
language = "English",
volume = "85",
pages = "174--183",
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TY - JOUR

T1 - Spindle assembly checkpoint MAD2 and CDC20 overexpressions and cell-in-cell formation in gastric cancer and its precursor lesions

AU - Kim, Younghye

AU - Choi, Jung-Woo

AU - Lee, Ju-Han

AU - Kim, Young Sik

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Overexpression of mitotic arrest deficient 2 (MAD2) and/or cell division cycle 20 (CDC20) in the spindle assembly checkpoint leads to chromosomal instability and aneuploidy. Cell-in-cell (CIC) structures are formed by the process where cancer or immune cells are internalized into adjacent host cancer cells. Here, we investigated the clinicopathological significances of spindle assembly checkpoint protein overexpression and CIC structures in 829 cases of normal, premalignant, and gastric cancer (GC) lesions. MAD2 and CDC20 expressions were significantly increased in intestinal metaplasia, low-grade dysplasia, high-grade dysplasia (HGD), and early GC than normal mucosa, and their expression levels were the highest in HGD. Interestingly, CDC20 immunohistochemistry specifically stained the outer cells of CIC structures, which were the most frequently observed in early GC. In univariate analyses, MAD2 and CDC20 overexpressions and CIC formation were associated with older age, intestinal histology, lower tumor-node-metastasis stage, and longer recurrence-free survival and cancer-specific survival of GC patients. In multivariate survival analyses, MAD2 and CDC20 overexpressions were associated with better recurrence-free survival (hazard ratio, 0.61; P = .012) and cancer-specific survival (hazard ratio, 0.63; P = .043), respectively. In conclusion, MAD2 and CDC20 are the most expressed in HGD, suggesting their roles in the early stage of gastric carcinogenesis, whereas their overexpressions in GC are associated with intestinal histology and favorable clinicopathological parameters, which may be useful for immunohistochemical classification of chromosomal instability–type GC. Moreover, CDC20 is a novel immunohistochemical marker for highlighting CIC structures.

AB - Overexpression of mitotic arrest deficient 2 (MAD2) and/or cell division cycle 20 (CDC20) in the spindle assembly checkpoint leads to chromosomal instability and aneuploidy. Cell-in-cell (CIC) structures are formed by the process where cancer or immune cells are internalized into adjacent host cancer cells. Here, we investigated the clinicopathological significances of spindle assembly checkpoint protein overexpression and CIC structures in 829 cases of normal, premalignant, and gastric cancer (GC) lesions. MAD2 and CDC20 expressions were significantly increased in intestinal metaplasia, low-grade dysplasia, high-grade dysplasia (HGD), and early GC than normal mucosa, and their expression levels were the highest in HGD. Interestingly, CDC20 immunohistochemistry specifically stained the outer cells of CIC structures, which were the most frequently observed in early GC. In univariate analyses, MAD2 and CDC20 overexpressions and CIC formation were associated with older age, intestinal histology, lower tumor-node-metastasis stage, and longer recurrence-free survival and cancer-specific survival of GC patients. In multivariate survival analyses, MAD2 and CDC20 overexpressions were associated with better recurrence-free survival (hazard ratio, 0.61; P = .012) and cancer-specific survival (hazard ratio, 0.63; P = .043), respectively. In conclusion, MAD2 and CDC20 are the most expressed in HGD, suggesting their roles in the early stage of gastric carcinogenesis, whereas their overexpressions in GC are associated with intestinal histology and favorable clinicopathological parameters, which may be useful for immunohistochemical classification of chromosomal instability–type GC. Moreover, CDC20 is a novel immunohistochemical marker for highlighting CIC structures.

KW - Aneuploidy

KW - CDC20

KW - Cell-in-cell structure

KW - Gastric cancer

KW - MAD2

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JO - Human Pathology

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