Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression: An NRG Oncology/Gynecologic Oncology Group study

Eric J. Devor, Jeffrey Miecznikowski, Brandon M. Schickling, Jesus Gonzalez-Bosquet, Heather A. Lankes, Premal Thaker, Peter A. Argenta, Michael L. Pearl, Susan L. Zweizig, Robert S. Mannel, Amy Brown, Nilsa C. Ramirez, Olga B. Ioffe, Kay J. Park, William T. Creasman, Michael J. Birrer, David Mutch, Kimberly K. Leslie

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Objective Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. Methods Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. Results Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. Conclusions Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.

Original languageEnglish (US)
Pages (from-to)648-653
Number of pages6
JournalGynecologic oncology
Volume147
Issue number3
DOIs
StatePublished - Dec 2017

Fingerprint

Endometrioid Carcinoma
MicroRNAs
Recurrence
Neoplasms
Adenocarcinoma
Carcinosarcoma
Atlases
Endometrial Neoplasms
Down-Regulation
Genome
Databases

Keywords

  • Endometrioid adenocarcinoma
  • NOTCH2
  • Recurrence
  • miR-181c

Cite this

Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression : An NRG Oncology/Gynecologic Oncology Group study. / Devor, Eric J.; Miecznikowski, Jeffrey; Schickling, Brandon M.; Gonzalez-Bosquet, Jesus; Lankes, Heather A.; Thaker, Premal; Argenta, Peter A.; Pearl, Michael L.; Zweizig, Susan L.; Mannel, Robert S.; Brown, Amy; Ramirez, Nilsa C.; Ioffe, Olga B.; Park, Kay J.; Creasman, William T.; Birrer, Michael J.; Mutch, David; Leslie, Kimberly K.

In: Gynecologic oncology, Vol. 147, No. 3, 12.2017, p. 648-653.

Research output: Contribution to journalArticle

Devor, EJ, Miecznikowski, J, Schickling, BM, Gonzalez-Bosquet, J, Lankes, HA, Thaker, P, Argenta, PA, Pearl, ML, Zweizig, SL, Mannel, RS, Brown, A, Ramirez, NC, Ioffe, OB, Park, KJ, Creasman, WT, Birrer, MJ, Mutch, D & Leslie, KK 2017, 'Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression: An NRG Oncology/Gynecologic Oncology Group study', Gynecologic oncology, vol. 147, no. 3, pp. 648-653. https://doi.org/10.1016/j.ygyno.2017.09.025
Devor, Eric J. ; Miecznikowski, Jeffrey ; Schickling, Brandon M. ; Gonzalez-Bosquet, Jesus ; Lankes, Heather A. ; Thaker, Premal ; Argenta, Peter A. ; Pearl, Michael L. ; Zweizig, Susan L. ; Mannel, Robert S. ; Brown, Amy ; Ramirez, Nilsa C. ; Ioffe, Olga B. ; Park, Kay J. ; Creasman, William T. ; Birrer, Michael J. ; Mutch, David ; Leslie, Kimberly K. / Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression : An NRG Oncology/Gynecologic Oncology Group study. In: Gynecologic oncology. 2017 ; Vol. 147, No. 3. pp. 648-653.
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abstract = "Objective Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. Methods Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. Results Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. Conclusions Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.",
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T1 - Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression

T2 - An NRG Oncology/Gynecologic Oncology Group study

AU - Devor, Eric J.

AU - Miecznikowski, Jeffrey

AU - Schickling, Brandon M.

AU - Gonzalez-Bosquet, Jesus

AU - Lankes, Heather A.

AU - Thaker, Premal

AU - Argenta, Peter A.

AU - Pearl, Michael L.

AU - Zweizig, Susan L.

AU - Mannel, Robert S.

AU - Brown, Amy

AU - Ramirez, Nilsa C.

AU - Ioffe, Olga B.

AU - Park, Kay J.

AU - Creasman, William T.

AU - Birrer, Michael J.

AU - Mutch, David

AU - Leslie, Kimberly K.

PY - 2017/12

Y1 - 2017/12

N2 - Objective Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. Methods Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. Results Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. Conclusions Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.

AB - Objective Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. Methods Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. Results Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. Conclusions Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.

KW - Endometrioid adenocarcinoma

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KW - Recurrence

KW - miR-181c

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