TY - JOUR
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 A.
AU - Weroha, Saravut J.
AU - Kalli, Kimberly R.
AU - Hartmann, Lynn C.
AU - Kaufmann, Scott H.
AU - Goode, Ellen L.
AU - Shridhar, Viji
N1 - Publisher Copyright:
© 2019
PY - 2019/9
Y1 - 2019/9
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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UR - http://www.scopus.com/inward/citedby.url?scp=85067186345&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2019.06.010
DO - 10.1016/j.ygyno.2019.06.010
M3 - Article
C2 - 31204077
AN - SCOPUS:85067186345
SN - 0090-8258
VL - 154
SP - 495
EP - 504
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 3
ER -