Genes associated with bowel metastases in ovarian cancer

Abstract

We identified 21 genes overexpressed in ovarian cancer (OC) bowel metastases compared to primary tumors. • High expression of these genes in primary OCs is associated with a need of complex bowel surgery and poor prognosis.• These genes may help identify potential therapeutic targets of malignant bowel obstruction in OC. a b s t r a c tObjective. 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 b .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. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

Recurrence-Associated Multi-RNA Signature to Predict Disease-Free Survival for Ovarian Cancer Patients

“…As for the prognostic genes not explored in the ceRNA network, most of them had been shown to be associated with the development and progression of OvCa or other cancers previously in the literature. For example, C1QTNF3 (C1q and TNF related 3) was found to be upregulated in bowel metastasis samples than primary OvCa [52]. ARID3A (ATrich interactive domain 3A) positivity was implied to be correlated with longer DFS and cancer-specific survival in patients with residual rectal cancer [53].…”

Expression and clinical implications of leucine‐rich repeat containing 15 (LRRC15) in osteosarcoma

“…In addition to our findings in osteosarcoma, other tumors of mesenchymal origin have also shown overexpression, including soft tissue sarcomas, melanoma, and glioblastoma. 15,16,18,18,30,31 LRRC15 has also shown marked overexpression within the cancer-associated fibroblasts known to promote carcinogenesis within the stroma. 13,32 In a very recent study, single-cell RNA Seq revealed elevated levels of LRRC15 positive cancer-associated fibroblasts correlated with a worse response to cancer immunotherapy.…”

“…The expression of LRRC15 was assessed by immunohistochemical (IHC) staining as previously described. 18,23 In brief, the TMA slides were baked for 1 h at 60°C before xylene deparaffinization and rehydration through graded ethanol (100% and 95%). After that, 3%…”

“…14,15 LRRC15 overexpression is quite specific for malignancy as it tends to be restricted to solid tumors and their cancer-associated stromal fibroblasts while sparing normal host tissue. [16][17][18] This overexpression has been shown to promote metastasis and progression in breast cancer, ovarian cancer, and soft tissue sarcomas. 15,18,19 As a transmembrane protein, LRRC15 has been reported as a robust and emerging therapeutic target for cancer treatment.…”

“…[16][17][18] This overexpression has been shown to promote metastasis and progression in breast cancer, ovarian cancer, and soft tissue sarcomas. 15,18,19 As a transmembrane protein, LRRC15 has been reported as a robust and emerging therapeutic target for cancer treatment. 13,15,19 Despite its emergence as a veritable marker of cancer-associated fibroblasts and sarcomas, its significance within osteosarcoma is unknown.…”