Genes associated with bowel metastases in ovarian cancer

Andrea Mariani, Chen Wang, Ann L Oberg, Shaun M. Riska, Michelle Torres, Joseph Kumka, Francesco Multinu, Gunisha Sagar, Debarshi Roy, Deok–Beom B. Jung, Qing Zhang, Tommaso Grassi, Daniel W Visscher, Vatsal P. Patel, Ling Jin, Julie K. Staub, William Arthur Cliby, Saravut (John) Weroha, Kimberly R. Kalli, Lynn C. Hartmann & 3 others Scott H Kaufmann, Ellen L Goode, Vijayalakshmi Shridhar

Research output: Contribution to journalArticle

Abstract

Objective: This study is designed to identify genes and pathways that could promote metastasis to the bowel in high-grade serous ovarian cancer (OC) and evaluate their associations with clinical outcomes. Methods: We performed RNA sequencing of OC primary tumors (PTs) and their corresponding bowel metastases (n = 21 discovery set; n = 18 replication set). Differentially expressed genes (DEGs) were those expressed at least 2-fold higher in bowel metastases (BMets) than PTs in at least 30% of patients (P <.05) with no increased expression in paired benign bowel tissue and were validated with quantitative reverse transcription PCR. Using an independent OC cohort (n = 333), associations between DEGs in PTs and surgical and clinical outcomes were performed. Immunohistochemistry and mouse xenograft studies were performed to confirm the role of LRRC15 in promoting metastasis. Results: Among 27 DEGs in the discovery set, 21 were confirmed in the replication set: SFRP2, Col11A1, LRRC15, ADAM12, ADAMTS12, MFAP5, LUM, PLPP4, FAP, POSTN, GRP, MMP11, MMP13, C1QTNF3, EPYC, DIO2, KCNA1, NETO1, NTM, MYH13, and PVALB. Higher expression of more than half of the genes in the PT was associated with an increased requirement for bowel resection at primary surgery and an inability to achieve complete cytoreduction. Increased expression of LRRC15 in BMets was confirmed by immunohistochemistry and knockdown of LRRC15 significantly inhibited tumor progression in mice. Conclusions: We identified 21 genes that are overexpressed in bowel metastases among patients with OC. Our findings will help select potential molecular targets for the prevention and treatment of malignant bowel obstruction in OC.

Original languageEnglish (US)
JournalGynecologic oncology
DOIs
StatePublished - Jan 1 2019

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Ovarian Neoplasms
Neoplasm Metastasis
Genes
Neoplasms
Immunohistochemistry
RNA Sequence Analysis
Genetic Association Studies
Heterografts
Reverse Transcription
Polymerase Chain Reaction

Keywords

  • Bowel metastasis
  • Differentially expressed genes
  • Extracellular matrix
  • Malignant bowel obstruction
  • Ovarian cancer

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

Cite this

Genes associated with bowel metastases in ovarian cancer. / Mariani, Andrea; Wang, Chen; Oberg, Ann L; Riska, Shaun M.; Torres, Michelle; Kumka, Joseph; Multinu, Francesco; Sagar, Gunisha; Roy, Debarshi; Jung, Deok–Beom B.; Zhang, Qing; Grassi, Tommaso; Visscher, Daniel W; Patel, Vatsal P.; Jin, Ling; Staub, Julie K.; Cliby, William Arthur; Weroha, Saravut (John); Kalli, Kimberly R.; Hartmann, Lynn C.; Kaufmann, Scott H; Goode, Ellen L; Shridhar, Vijayalakshmi.

In: Gynecologic oncology, 01.01.2019.

Research output: Contribution to journalArticle

Mariani, A, Wang, C, Oberg, AL, Riska, SM, Torres, M, Kumka, J, Multinu, F, Sagar, G, Roy, D, Jung, DBB, Zhang, Q, Grassi, T, Visscher, DW, Patel, VP, Jin, L, Staub, JK, Cliby, WA, Weroha, SJ, Kalli, KR, Hartmann, LC, Kaufmann, SH, Goode, EL & Shridhar, V 2019, 'Genes associated with bowel metastases in ovarian cancer', Gynecologic oncology. https://doi.org/10.1016/j.ygyno.2019.06.010
Mariani, Andrea ; Wang, Chen ; Oberg, Ann L ; Riska, Shaun M. ; Torres, Michelle ; Kumka, Joseph ; Multinu, Francesco ; Sagar, Gunisha ; Roy, Debarshi ; Jung, Deok–Beom B. ; Zhang, Qing ; Grassi, Tommaso ; Visscher, Daniel W ; Patel, Vatsal P. ; Jin, Ling ; Staub, Julie K. ; Cliby, William Arthur ; Weroha, Saravut (John) ; Kalli, Kimberly R. ; Hartmann, Lynn C. ; Kaufmann, Scott H ; Goode, Ellen L ; Shridhar, Vijayalakshmi. / Genes associated with bowel metastases in ovarian cancer. In: Gynecologic oncology. 2019.
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abstract = "Objective: This study is designed to identify genes and pathways that could promote metastasis to the bowel in high-grade serous ovarian cancer (OC) and evaluate their associations with clinical outcomes. Methods: We performed RNA sequencing of OC primary tumors (PTs) and their corresponding bowel metastases (n = 21 discovery set; n = 18 replication set). Differentially expressed genes (DEGs) were those expressed at least 2-fold higher in bowel metastases (BMets) than PTs in at least 30{\%} of patients (P <.05) with no increased expression in paired benign bowel tissue and were validated with quantitative reverse transcription PCR. Using an independent OC cohort (n = 333), associations between DEGs in PTs and surgical and clinical outcomes were performed. Immunohistochemistry and mouse xenograft studies were performed to confirm the role of LRRC15 in promoting metastasis. Results: Among 27 DEGs in the discovery set, 21 were confirmed in the replication set: SFRP2, Col11A1, LRRC15, ADAM12, ADAMTS12, MFAP5, LUM, PLPP4, FAP, POSTN, GRP, MMP11, MMP13, C1QTNF3, EPYC, DIO2, KCNA1, NETO1, NTM, MYH13, and PVALB. Higher expression of more than half of the genes in the PT was associated with an increased requirement for bowel resection at primary surgery and an inability to achieve complete cytoreduction. Increased expression of LRRC15 in BMets was confirmed by immunohistochemistry and knockdown of LRRC15 significantly inhibited tumor progression in mice. Conclusions: We identified 21 genes that are overexpressed in bowel metastases among patients with OC. Our findings will help select potential molecular targets for the prevention and treatment of malignant bowel obstruction in OC.",
keywords = "Bowel metastasis, Differentially expressed genes, Extracellular matrix, Malignant bowel obstruction, Ovarian cancer",
author = "Andrea Mariani and Chen Wang and Oberg, {Ann L} and Riska, {Shaun M.} and Michelle Torres and Joseph Kumka and Francesco Multinu and Gunisha Sagar and Debarshi Roy and Jung, {Deok–Beom B.} and Qing Zhang and Tommaso Grassi and Visscher, {Daniel W} and Patel, {Vatsal P.} and Ling Jin and Staub, {Julie K.} and Cliby, {William Arthur} and Weroha, {Saravut (John)} and Kalli, {Kimberly R.} and Hartmann, {Lynn C.} and Kaufmann, {Scott H} and Goode, {Ellen L} and Vijayalakshmi Shridhar",
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T1 - Genes associated with bowel metastases in ovarian cancer

AU - Mariani, Andrea

AU - Wang, Chen

AU - Oberg, Ann L

AU - Riska, Shaun M.

AU - Torres, Michelle

AU - Kumka, Joseph

AU - Multinu, Francesco

AU - Sagar, Gunisha

AU - Roy, Debarshi

AU - Jung, Deok–Beom B.

AU - Zhang, Qing

AU - Grassi, Tommaso

AU - Visscher, Daniel W

AU - Patel, Vatsal P.

AU - Jin, Ling

AU - Staub, Julie K.

AU - Cliby, William Arthur

AU - Weroha, Saravut (John)

AU - Kalli, Kimberly R.

AU - Hartmann, Lynn C.

AU - Kaufmann, Scott H

AU - Goode, Ellen L

AU - Shridhar, Vijayalakshmi

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Objective: This study is designed to identify genes and pathways that could promote metastasis to the bowel in high-grade serous ovarian cancer (OC) and evaluate their associations with clinical outcomes. Methods: We performed RNA sequencing of OC primary tumors (PTs) and their corresponding bowel metastases (n = 21 discovery set; n = 18 replication set). Differentially expressed genes (DEGs) were those expressed at least 2-fold higher in bowel metastases (BMets) than PTs in at least 30% of patients (P <.05) with no increased expression in paired benign bowel tissue and were validated with quantitative reverse transcription PCR. Using an independent OC cohort (n = 333), associations between DEGs in PTs and surgical and clinical outcomes were performed. Immunohistochemistry and mouse xenograft studies were performed to confirm the role of LRRC15 in promoting metastasis. Results: Among 27 DEGs in the discovery set, 21 were confirmed in the replication set: SFRP2, Col11A1, LRRC15, ADAM12, ADAMTS12, MFAP5, LUM, PLPP4, FAP, POSTN, GRP, MMP11, MMP13, C1QTNF3, EPYC, DIO2, KCNA1, NETO1, NTM, MYH13, and PVALB. Higher expression of more than half of the genes in the PT was associated with an increased requirement for bowel resection at primary surgery and an inability to achieve complete cytoreduction. Increased expression of LRRC15 in BMets was confirmed by immunohistochemistry and knockdown of LRRC15 significantly inhibited tumor progression in mice. Conclusions: We identified 21 genes that are overexpressed in bowel metastases among patients with OC. Our findings will help select potential molecular targets for the prevention and treatment of malignant bowel obstruction in OC.

AB - Objective: This study is designed to identify genes and pathways that could promote metastasis to the bowel in high-grade serous ovarian cancer (OC) and evaluate their associations with clinical outcomes. Methods: We performed RNA sequencing of OC primary tumors (PTs) and their corresponding bowel metastases (n = 21 discovery set; n = 18 replication set). Differentially expressed genes (DEGs) were those expressed at least 2-fold higher in bowel metastases (BMets) than PTs in at least 30% of patients (P <.05) with no increased expression in paired benign bowel tissue and were validated with quantitative reverse transcription PCR. Using an independent OC cohort (n = 333), associations between DEGs in PTs and surgical and clinical outcomes were performed. Immunohistochemistry and mouse xenograft studies were performed to confirm the role of LRRC15 in promoting metastasis. Results: Among 27 DEGs in the discovery set, 21 were confirmed in the replication set: SFRP2, Col11A1, LRRC15, ADAM12, ADAMTS12, MFAP5, LUM, PLPP4, FAP, POSTN, GRP, MMP11, MMP13, C1QTNF3, EPYC, DIO2, KCNA1, NETO1, NTM, MYH13, and PVALB. Higher expression of more than half of the genes in the PT was associated with an increased requirement for bowel resection at primary surgery and an inability to achieve complete cytoreduction. Increased expression of LRRC15 in BMets was confirmed by immunohistochemistry and knockdown of LRRC15 significantly inhibited tumor progression in mice. Conclusions: We identified 21 genes that are overexpressed in bowel metastases among patients with OC. Our findings will help select potential molecular targets for the prevention and treatment of malignant bowel obstruction in OC.

KW - Bowel metastasis

KW - Differentially expressed genes

KW - Extracellular matrix

KW - Malignant bowel obstruction

KW - Ovarian cancer

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