Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects

Oncotarget. 2016 Jul 5;7(27):41959-41973. doi: 10.18632/oncotarget.9747.

Abstract

The classification of bronchopulmonary neuroendocrine neoplasms (BP-NEN) into four tumor entities (typical carcinoids (TC), atypical carcinoids (AC), small cell lung cancers (SCLC), large cell neuroendocrine lung carcinomas (LCNEC)) is difficult to perform accurately, but important for prognostic statements and therapeutic management decisions. In this regard, we compared the expression of three proliferation markers, Ki-67, Topoisomerase II alpha (TOP2A), and RacGAP1, in a series of tumor samples from 104 BP-NEN patients (24 TC, 21 AC, 52 SCLC, 7 LCNEC) using different evaluation methods (immunohistochemistry (IHC): Average evaluation, Hotspot evaluation, digital image analysis; RT-qPCR).The results indicated that all three markers had increased protein and mRNA expression with poorer differentiation and correlated well with each other, as well as with grading, staging, and poor survival. Compared with Ki-67 and TOP2A, RacGAP1 allowed for a clearer prognostic statement. The cut-off limits obtained for Ki-67-Average (IHC) were TC-AC 1.5, AC-SCLC 19, and AC-LCNEC 23.5. The Hotspot evaluation generated equal to higher, the digital image analysis generally lower between-entity cut-off limits.All three markers enabled a clear-cut differentiation between the BP-NEN entities, and all methods evaluated were suitable for marker assessment. However, to define optimal cut-off limits, the Ki-67 evaluation methods should be standardized. RacGAP1 appeared to be a new marker with great potential.

Keywords: IHC/RT-qPCR; Ki-67; RacGAP1; lung neuroendocrine neoplasms; topoisomerase 2 alpha.

Publication types

  • Comparative Study

MeSH terms

  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoid Tumor / diagnosis
  • Carcinoid Tumor / genetics
  • Carcinoid Tumor / metabolism
  • Carcinoma, Large Cell / diagnosis
  • Carcinoma, Large Cell / genetics
  • Carcinoma, Large Cell / metabolism
  • DNA Topoisomerases, Type II / genetics
  • DNA Topoisomerases, Type II / metabolism*
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Humans
  • Kaplan-Meier Estimate
  • Ki-67 Antigen / genetics
  • Ki-67 Antigen / metabolism*
  • Lung / drug effects
  • Lung / pathology
  • Lung / radiation effects
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Neoplasm Grading
  • Neoplasm Staging
  • Neuroendocrine Tumors / diagnosis
  • Neuroendocrine Tumors / genetics
  • Neuroendocrine Tumors / metabolism*
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins / metabolism*
  • Prognosis
  • Small Cell Lung Carcinoma / diagnosis
  • Small Cell Lung Carcinoma / genetics
  • Small Cell Lung Carcinoma / metabolism

Substances

  • Biomarkers, Tumor
  • GTPase-Activating Proteins
  • Ki-67 Antigen
  • Poly-ADP-Ribose Binding Proteins
  • mgcRacGAP
  • DNA Topoisomerases, Type II
  • TOP2A protein, human