Targeted next-generation sequencing identifies actionable targets in estrogen receptor positive and estrogen receptor negative endometriod endometrial cancer

Siti Syazani Suhaimi, Nurul Syakima Ab Mutalib, Sheau S. Khor, Reena Rahayu Md Zain, Saiful Effendi Syafruddin, Nadiah Abu, Ahmad Zailani Hatta Mohd Dali, A. Rahman A. Jamal

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Abstract

Endometrioid endometrial cancer (EEC) is the commonest form of endometrial cancer and can be divided into estrogen receptor (ER) positive and negative subtypes. The mutational profiles of EEC have been shown to aid in tailoring treatment; however, little is known about the differences between the gene mutation profiles between these two subtypes. This study aims to investigate the gene mutation profile in ER positive and negative EEC, and to further elucidate the role of WHSC1 mutations in this cancer. EEC and normal endometrial tissues were obtained from 29 patients and subjected to next-generation sequencing (NGS) using Ion Ampliseq Comprehensive Cancer PanelTM targeting 409 cancer related. A total of 741 non-synonymous alterations were identified from 272 genes in ER positive subtype while 448 non-synonymous variants were identified from 221 genes in ER negative subtype. PTEN is the most frequently altered gene in ER positive subtype (64%, 7/11) while ARID1A is the most frequently altered gene in ER negative subtype (50%, 4/8). We also identified alterations in ERRB3 (36%, 4/11), GNAS (36%, 4/11), and WHSC1 (27%, 3/11) in the ER positive subtype. WHSC1 R1126H and L1268P were shown to significantly increase cell viability, proliferation, migration, and survival. In addition, reduction in ER expression sensitized EEC-1 cell with WHSC1 L1268P mutant to Fulvestrant treatment. We revealed the mutational spectra of ER positive and ER negative EEC that could lead to better understanding of the biological mechanisms of endometrial cancer and may ultimately result in improvement of treatment options and patient prognosis.

Original languageEnglish
Article number750
JournalFrontiers in Pharmacology
Volume9
Issue numberJUN
DOIs
Publication statusPublished - 13 Jul 2018

Fingerprint

Endometrial Neoplasms
Estrogen Receptors
Genes
Mutation
Neoplasms
Cell Survival
Therapeutics
Cell Proliferation
Ions
Survival

Keywords

  • Endometrial cancer
  • Endometrioid subtype
  • Estrogen receptor
  • Fulvestrant
  • Next-generation sequencing
  • WHSC1

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

@article{614e76bdbd5a47e2b2bae03d66380f37,
title = "Targeted next-generation sequencing identifies actionable targets in estrogen receptor positive and estrogen receptor negative endometriod endometrial cancer",
abstract = "Endometrioid endometrial cancer (EEC) is the commonest form of endometrial cancer and can be divided into estrogen receptor (ER) positive and negative subtypes. The mutational profiles of EEC have been shown to aid in tailoring treatment; however, little is known about the differences between the gene mutation profiles between these two subtypes. This study aims to investigate the gene mutation profile in ER positive and negative EEC, and to further elucidate the role of WHSC1 mutations in this cancer. EEC and normal endometrial tissues were obtained from 29 patients and subjected to next-generation sequencing (NGS) using Ion Ampliseq Comprehensive Cancer PanelTM targeting 409 cancer related. A total of 741 non-synonymous alterations were identified from 272 genes in ER positive subtype while 448 non-synonymous variants were identified from 221 genes in ER negative subtype. PTEN is the most frequently altered gene in ER positive subtype (64{\%}, 7/11) while ARID1A is the most frequently altered gene in ER negative subtype (50{\%}, 4/8). We also identified alterations in ERRB3 (36{\%}, 4/11), GNAS (36{\%}, 4/11), and WHSC1 (27{\%}, 3/11) in the ER positive subtype. WHSC1 R1126H and L1268P were shown to significantly increase cell viability, proliferation, migration, and survival. In addition, reduction in ER expression sensitized EEC-1 cell with WHSC1 L1268P mutant to Fulvestrant treatment. We revealed the mutational spectra of ER positive and ER negative EEC that could lead to better understanding of the biological mechanisms of endometrial cancer and may ultimately result in improvement of treatment options and patient prognosis.",
keywords = "Endometrial cancer, Endometrioid subtype, Estrogen receptor, Fulvestrant, Next-generation sequencing, WHSC1",
author = "Suhaimi, {Siti Syazani} and {Ab Mutalib}, {Nurul Syakima} and Khor, {Sheau S.} and {Md Zain}, {Reena Rahayu} and Syafruddin, {Saiful Effendi} and Nadiah Abu and Dali, {Ahmad Zailani Hatta Mohd} and {A. Jamal}, {A. Rahman}",
year = "2018",
month = "7",
day = "13",
doi = "10.3389/fphar.2018.00750",
language = "English",
volume = "9",
journal = "Frontiers in Pharmacology",
issn = "1663-9812",
publisher = "Frontiers Media S. A.",
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T1 - Targeted next-generation sequencing identifies actionable targets in estrogen receptor positive and estrogen receptor negative endometriod endometrial cancer

AU - Suhaimi, Siti Syazani

AU - Ab Mutalib, Nurul Syakima

AU - Khor, Sheau S.

AU - Md Zain, Reena Rahayu

AU - Syafruddin, Saiful Effendi

AU - Abu, Nadiah

AU - Dali, Ahmad Zailani Hatta Mohd

AU - A. Jamal, A. Rahman

PY - 2018/7/13

Y1 - 2018/7/13

N2 - Endometrioid endometrial cancer (EEC) is the commonest form of endometrial cancer and can be divided into estrogen receptor (ER) positive and negative subtypes. The mutational profiles of EEC have been shown to aid in tailoring treatment; however, little is known about the differences between the gene mutation profiles between these two subtypes. This study aims to investigate the gene mutation profile in ER positive and negative EEC, and to further elucidate the role of WHSC1 mutations in this cancer. EEC and normal endometrial tissues were obtained from 29 patients and subjected to next-generation sequencing (NGS) using Ion Ampliseq Comprehensive Cancer PanelTM targeting 409 cancer related. A total of 741 non-synonymous alterations were identified from 272 genes in ER positive subtype while 448 non-synonymous variants were identified from 221 genes in ER negative subtype. PTEN is the most frequently altered gene in ER positive subtype (64%, 7/11) while ARID1A is the most frequently altered gene in ER negative subtype (50%, 4/8). We also identified alterations in ERRB3 (36%, 4/11), GNAS (36%, 4/11), and WHSC1 (27%, 3/11) in the ER positive subtype. WHSC1 R1126H and L1268P were shown to significantly increase cell viability, proliferation, migration, and survival. In addition, reduction in ER expression sensitized EEC-1 cell with WHSC1 L1268P mutant to Fulvestrant treatment. We revealed the mutational spectra of ER positive and ER negative EEC that could lead to better understanding of the biological mechanisms of endometrial cancer and may ultimately result in improvement of treatment options and patient prognosis.

AB - Endometrioid endometrial cancer (EEC) is the commonest form of endometrial cancer and can be divided into estrogen receptor (ER) positive and negative subtypes. The mutational profiles of EEC have been shown to aid in tailoring treatment; however, little is known about the differences between the gene mutation profiles between these two subtypes. This study aims to investigate the gene mutation profile in ER positive and negative EEC, and to further elucidate the role of WHSC1 mutations in this cancer. EEC and normal endometrial tissues were obtained from 29 patients and subjected to next-generation sequencing (NGS) using Ion Ampliseq Comprehensive Cancer PanelTM targeting 409 cancer related. A total of 741 non-synonymous alterations were identified from 272 genes in ER positive subtype while 448 non-synonymous variants were identified from 221 genes in ER negative subtype. PTEN is the most frequently altered gene in ER positive subtype (64%, 7/11) while ARID1A is the most frequently altered gene in ER negative subtype (50%, 4/8). We also identified alterations in ERRB3 (36%, 4/11), GNAS (36%, 4/11), and WHSC1 (27%, 3/11) in the ER positive subtype. WHSC1 R1126H and L1268P were shown to significantly increase cell viability, proliferation, migration, and survival. In addition, reduction in ER expression sensitized EEC-1 cell with WHSC1 L1268P mutant to Fulvestrant treatment. We revealed the mutational spectra of ER positive and ER negative EEC that could lead to better understanding of the biological mechanisms of endometrial cancer and may ultimately result in improvement of treatment options and patient prognosis.

KW - Endometrial cancer

KW - Endometrioid subtype

KW - Estrogen receptor

KW - Fulvestrant

KW - Next-generation sequencing

KW - WHSC1

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