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Gynecol Oncol. 2019 Sep;154(3):495-504. doi: 10.1016/j.ygyno.2019.06.010. Epub 2019 Jun 14.

Genes associated with bowel metastases in ovarian cancer.

Author information

1
Department of Obstetrics and Gynecology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
2
Department of Obstetrics and Gynecology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
3
Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
4
Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
5
Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
6
Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
7
Department of Obstetrics and Gynecology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address: shridhar.vijayalakshmi@mayo.edu.

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

PMID:
31204077
DOI:
10.1016/j.ygyno.2019.06.010
[Indexed for MEDLINE]
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