PI3K Pathway Effectors pAKT and FOXO1 as Novel Markers of Endometrioid Intraepithelial Neoplasia

Amanda L. Strickland, Glorimar Rivera, Elena Lucas, George John, Ileana Cuevas, Diego H. Castrillon

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4 Citations (Scopus)

Abstract

The diagnosis of endometrioid intraepithelial neoplasia (EIN) is challenging owing to limited sampling, hormonal status, and other confounding histologic variables. Markers such as PTEN or PAX2 can delineate EIN in some cases, but are not wholly reliable. Clearly, new markers of EIN are needed. We explored several potential markers of EIN based rationally on molecular pathways most frequently misregulated in endometrial cancer: the 3-phosphoinositide kinase (PI3K)/AKT, β-catenin, and mismatch repair pathways. We studied PTEN, PAX2, β-catenin, and MLH1, in conjunction with 2 new markers - FOXO1 and phosphorylated AKT (pAKT) - not previously investigated in EIN. Benign (n=14) and EIN (n=35) endometria were analyzed by immunohistochemistry. Staining patterns were interpreted, tabulated, and scored by "clonal distinctiveness" in neoplastic lesions; that is, pattern alterations relative to normal glands. In normal endometria, FOXO1 was cytoplasmic in proliferative phase, but nuclear in secretory phase, showing that PI3K/FOXO1 participates in endometrial cycling and that FOXO1 is a readout of PI3K status. pAKT expression was low across normal endometria. FOXO1 or pAKT expression was altered in the majority of EINs (27/35, 77%), with FOXO1 and pAKT being co-altered only in some (20/35, 57%). β-catenin or MLH1 also exhibited clonal distinctiveness in EINs, showing that these are also useful markers in some cases. This is the first study to demonstrate the potential of pAKT and FOXO1 as biomarkers in the histopathologic evaluation of EIN. However, variability in expression poses challenges in interpretation.

Original languageEnglish (US)
JournalInternational Journal of Gynecological Pathology
DOIs
StateAccepted/In press - Jan 1 2018

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Phosphatidylinositol 3-Kinases
Catenins
Endometrium
Neoplasms
DNA Mismatch Repair
1-Phosphatidylinositol 4-Kinase
Confounding Factors (Epidemiology)
Endometrial Neoplasms
Biomarkers
Immunohistochemistry
Staining and Labeling

Keywords

  • Biomarker
  • Endometrioid intraepithelial neoplasia
  • Endometrium
  • Neoplasia

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Obstetrics and Gynecology

Cite this

@article{aa13e8ee021449948b1c5deb708e8015,
title = "PI3K Pathway Effectors pAKT and FOXO1 as Novel Markers of Endometrioid Intraepithelial Neoplasia",
abstract = "The diagnosis of endometrioid intraepithelial neoplasia (EIN) is challenging owing to limited sampling, hormonal status, and other confounding histologic variables. Markers such as PTEN or PAX2 can delineate EIN in some cases, but are not wholly reliable. Clearly, new markers of EIN are needed. We explored several potential markers of EIN based rationally on molecular pathways most frequently misregulated in endometrial cancer: the 3-phosphoinositide kinase (PI3K)/AKT, β-catenin, and mismatch repair pathways. We studied PTEN, PAX2, β-catenin, and MLH1, in conjunction with 2 new markers - FOXO1 and phosphorylated AKT (pAKT) - not previously investigated in EIN. Benign (n=14) and EIN (n=35) endometria were analyzed by immunohistochemistry. Staining patterns were interpreted, tabulated, and scored by {"}clonal distinctiveness{"} in neoplastic lesions; that is, pattern alterations relative to normal glands. In normal endometria, FOXO1 was cytoplasmic in proliferative phase, but nuclear in secretory phase, showing that PI3K/FOXO1 participates in endometrial cycling and that FOXO1 is a readout of PI3K status. pAKT expression was low across normal endometria. FOXO1 or pAKT expression was altered in the majority of EINs (27/35, 77{\%}), with FOXO1 and pAKT being co-altered only in some (20/35, 57{\%}). β-catenin or MLH1 also exhibited clonal distinctiveness in EINs, showing that these are also useful markers in some cases. This is the first study to demonstrate the potential of pAKT and FOXO1 as biomarkers in the histopathologic evaluation of EIN. However, variability in expression poses challenges in interpretation.",
keywords = "Biomarker, Endometrioid intraepithelial neoplasia, Endometrium, Neoplasia",
author = "Strickland, {Amanda L.} and Glorimar Rivera and Elena Lucas and George John and Ileana Cuevas and Castrillon, {Diego H.}",
year = "2018",
month = "1",
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doi = "10.1097/PGP.0000000000000549",
language = "English (US)",
journal = "International Journal of Gynecological Pathology",
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T1 - PI3K Pathway Effectors pAKT and FOXO1 as Novel Markers of Endometrioid Intraepithelial Neoplasia

AU - Strickland, Amanda L.

AU - Rivera, Glorimar

AU - Lucas, Elena

AU - John, George

AU - Cuevas, Ileana

AU - Castrillon, Diego H.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - The diagnosis of endometrioid intraepithelial neoplasia (EIN) is challenging owing to limited sampling, hormonal status, and other confounding histologic variables. Markers such as PTEN or PAX2 can delineate EIN in some cases, but are not wholly reliable. Clearly, new markers of EIN are needed. We explored several potential markers of EIN based rationally on molecular pathways most frequently misregulated in endometrial cancer: the 3-phosphoinositide kinase (PI3K)/AKT, β-catenin, and mismatch repair pathways. We studied PTEN, PAX2, β-catenin, and MLH1, in conjunction with 2 new markers - FOXO1 and phosphorylated AKT (pAKT) - not previously investigated in EIN. Benign (n=14) and EIN (n=35) endometria were analyzed by immunohistochemistry. Staining patterns were interpreted, tabulated, and scored by "clonal distinctiveness" in neoplastic lesions; that is, pattern alterations relative to normal glands. In normal endometria, FOXO1 was cytoplasmic in proliferative phase, but nuclear in secretory phase, showing that PI3K/FOXO1 participates in endometrial cycling and that FOXO1 is a readout of PI3K status. pAKT expression was low across normal endometria. FOXO1 or pAKT expression was altered in the majority of EINs (27/35, 77%), with FOXO1 and pAKT being co-altered only in some (20/35, 57%). β-catenin or MLH1 also exhibited clonal distinctiveness in EINs, showing that these are also useful markers in some cases. This is the first study to demonstrate the potential of pAKT and FOXO1 as biomarkers in the histopathologic evaluation of EIN. However, variability in expression poses challenges in interpretation.

AB - The diagnosis of endometrioid intraepithelial neoplasia (EIN) is challenging owing to limited sampling, hormonal status, and other confounding histologic variables. Markers such as PTEN or PAX2 can delineate EIN in some cases, but are not wholly reliable. Clearly, new markers of EIN are needed. We explored several potential markers of EIN based rationally on molecular pathways most frequently misregulated in endometrial cancer: the 3-phosphoinositide kinase (PI3K)/AKT, β-catenin, and mismatch repair pathways. We studied PTEN, PAX2, β-catenin, and MLH1, in conjunction with 2 new markers - FOXO1 and phosphorylated AKT (pAKT) - not previously investigated in EIN. Benign (n=14) and EIN (n=35) endometria were analyzed by immunohistochemistry. Staining patterns were interpreted, tabulated, and scored by "clonal distinctiveness" in neoplastic lesions; that is, pattern alterations relative to normal glands. In normal endometria, FOXO1 was cytoplasmic in proliferative phase, but nuclear in secretory phase, showing that PI3K/FOXO1 participates in endometrial cycling and that FOXO1 is a readout of PI3K status. pAKT expression was low across normal endometria. FOXO1 or pAKT expression was altered in the majority of EINs (27/35, 77%), with FOXO1 and pAKT being co-altered only in some (20/35, 57%). β-catenin or MLH1 also exhibited clonal distinctiveness in EINs, showing that these are also useful markers in some cases. This is the first study to demonstrate the potential of pAKT and FOXO1 as biomarkers in the histopathologic evaluation of EIN. However, variability in expression poses challenges in interpretation.

KW - Biomarker

KW - Endometrioid intraepithelial neoplasia

KW - Endometrium

KW - Neoplasia

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