Fusion gene distribution among grades 1, 2, and 3 patients with EC
The fusion gene distribution among different grades of patients with EC is shown in Figure 3. The fusion genes of grade 1 patients with EC, including AC024084.1--AC009784.3, BMPR1B--PDLIM5, and MT-ATP6--MT-CO2, are shown in Figure 3A. The fusion genes of grade 2 patients with EC, including C15orf57--CBX3, CCDC80--COL1A1, and DPH7--PTP4A3, are shown in Figure 3B. The fusion genes of grade 3 patients with EC, including BMPR1B--PDLIM5, C15orf57--CBX3, and COL6A3--COL1A1, are shown in Figure 3C. These results indicate that the fusion genes RP11–123O10.4--GRIP1, RP11–444D3.1--SOX5, RP11–680G10.1--GSE1, RP11–96H19.1--RP11–446N19.1, and NRIP1--AF127936.7 were found in all grades of EC, while DPH7--PTP4A3 is found only in grades 2 and 3 EC.
Fusion gene distribution in recurrent and non-recurrent EC
The fusion gene distributions were different between recurrent and non-recurrent EC, as shown in Figure 4. The diagnosis of recurrence should be adjusted by abdominal, pelvic, and/or chest computed tomography or a physical exam based on the National Comprehensive Cancer Network (NCCN) guidelines. The fusion genes in patients with recurrent EC, including AC024084.1--AC009784.3, BMPR1B--PDLIM5, and MT-ATP6--MT-CO2, are shown in Figure 4A. The fusion genes in patients with non-recurrent EC, including BMPR1B--PDLIM5, C15orf57--CBX3, and COL6A3--COL1A1, are shown in Figure 4B. These results indicate that the fusion genes RP11–123O10.4--GRIP1, RP11–444D3.1--SOX5, RP11–680G10.1--GSE1, RP11–96H19.1--RP11–446N19.1, and NRIP1--AF127936.7 are over-expressed in non-recurrent EC, while DPH7--PTP4A3 is found in recurrent EC.
Fusion genes are hybrid genes that combine parts of two or more original genes, which are formed as a result of chromosomal rearrangements or abnormal transcription and have been shown to act as drivers of malignant transformation and progression in leukaemic tumors, neuroblastoma, and endometrial stromal sarcoma.[7,8] Fusion genes are also used as diagnostic and prognostic markers to confirm cancer diagnosis and to monitor the response to molecular therapies. Thus, to identify and verify the fusion genes of EC is of great importance.
To date, the study of fusion genes of uterine tumors have focused on endometrial stromal sarcoma-associated genomic rearrangements, including BRD8-PHF1,MBTD1-CXorf67,JAZF1-SUZ12, JAZF1-PHF1, EPC1-PHF1, and TSNAX-DISC1, which proved that fusion genes play essential roles in diagnosis, treatment, and prognosis.[7,10,18,19] In fact, there are few studies on fusion genes of endometrioid adenocarcinoma.
In this study, we proved that fusion genes were found in endometrioid adenocarcinoma and that the distribution of the fusion genes of endometrioid adenocarcinoma varied. We first showed that RP11–123O10.4--GRIP1, RP11–444D3.1--SOX5, RP11–680G10.1--GSE1, RP11–96H19.1--RP11–446N19.1, NRIP1--AF127936.7, and DPH7--PTP4A3 had high fusion rates and were over-expressed at high levels in patients with EC, suggesting that these fusion genes might be related to tumorigenesis and prognosis.
Further study of these six fusion genes with high fusion rates revealed that these fusion genes can be detected, while their biological functions remain unclear. RP11–123O10.4--GRIP1 was the fusion gene with the highest fusion rate (approximately 89.29%). RP11–123O10.4 is a lncRNA located on chromosome 12, and only one variant was found. lncRNAs are a set of non-protein-coding transcripts longer than 200 nucleotides that play vital roles in cancer proliferation and drug resistance. GRIP1 belongs to the p160 steroid receptor co-activator family that plays essential roles in nuclear receptor-dependent transcriptional regulation. GRIP1 is an mRNA located on chromosome 12 and contains two variants. Previous studies have shown that GRIP1 plays an essential role in cell proliferation. However, the biological function of RP11–123O10.4--GRIP1 remains unclear.
The fusion rate of RP11–444D3.1--SOX5 was 61%. RP11–444D3.1 is a lncRNA located on chromosome 12, and two variants were found. SOX5 is an mRNA located on chromosome 12 and contains three variants. SOX5 encodes a member of the SRY-related HMG-box family of transcription factors involved in the determination of cell fate and the regulation of embryonic development. As a nuclear transcription factor, the high expression of SOX5 is detected in many malignant tumors. The aberrant expression of SOX5 can promote the epithelial-mesenchymal transition, proliferation, invasion, and migration of cancers by targeting different downstream genes, such as Twist1, Snail, secreted protein acidic and rich in cysteine, and microphthalmia-associated transcription factor, as well as up-regulating the protein abundance of p27, β-catenin, etc.[23,24]
The fusion rate of RP11–680G10.1--GSE1 was 50%. RP11–680G10.1 is a lncRNA located on chromosome 16, and one variant was found. GSE1 is an mRNA located on chromosome 16 and contains two variants. GSE1, also known as KIAA0182, is a novel protein that has been isolated and identified by ion trap mass spectrometry. GSE1 is a proline-rich protein, and its estimated molecular mass is 136,000 kDa. GSE1 can mediate the progression of breast cancer in vitro. GSE1 overexpression in breast cancer and the knockdown of GSE1 significantly suppressed breast cancer cell proliferation, migration, and invasion. Furthermore, GSE1 was identified as a direct target of miR-489-5p, which is significantly reduced in breast cancer tissues. In addition, the forced expression of miR-489-5p suppressed breast cancer cell proliferation, migration, and invasion. Moreover, the depletion of GSE1 by siRNAs significantly abrogated the enhanced proliferation, migration, and invasion of breast cancer cells consequent to miR-489-5p depletion.
The fusion rate of NRIP1--AF127936.7 was 43%. NRIP1 is an mRNA located on chromosome 21, and two variants were found. AF127936.7 is located on chromosome 21 and contains two variants. NRIP1 is a transcriptional co-regulator (also known as RIP140) that plays very important physiological roles by finely tuning the activity of a large number of transcription factors. Noticeably, the RIP140 gene has been shown to be involved in the regulation of energy expenditure, mammary gland development, and intestinal homeostasis as well as behavior and cognition. RIP140 is also involved in the regulation of various oncogenic signaling pathways and participates in the development and progression of solid tumors. However, there are few studies on the AF127936.7 gene.
The fusion rate of RP11–96H19.1--RP11–446N19.1 was 39%. RP11–96H19.1 is a lncRNA located on chromosome 12, and two variants were found. RP11–446N19.1 is a lncRNA located on chromosome 12 and contains two variants. However, the functions of RP11–96H19.1 and RP11–446N19.1 remain unclear.
The fusion rate of DPH7--PTP4A3 was 32%. DPH7 is an mRNA located on chromosome 9, and one variant was found. PTP4A3 is an mRNA located on chromosome 8 and contains one variant. The membrane-associated intracellular protein tyrosine phosphatase PTP4A3 is over-expressed in human colorectal cancer and contributes to cell migration and invasion. However, few studies have illustrated the biological functions of DPH7.
In general, the detection of fusion genes might be recognized as a promising clinical tool for the diagnosis and staging classification of EC. Our present study indicates that fusion genes can be found in EC and play a key role in contributing to the progression of EC. We suggest that NRIP1--AF127936.7 and DPH7--PTP4A3 may be potential candidates for a new genetic and an epigenetic marker, respectively, in EC.
In this study, the fusion genes RP11–123O10.4--GRIP1, RP11–444D3.1--SOX5, RP11–680G10.1--GSE1, NRIP1--AF127936.7, RP11–96H19.1--RP11–446N19.1, and DPH7--PTP4A3 were proved to have a high fusion rate in EC. RP11–123O10.4--GRIP1, RP11–444D3.1--SOX5, RP11–680G10.1--GSE1, and RP11–96H19.1--RP11–446N19.1 might be related to tumorigenesis, while NRIP1--AF127936.7 and DPH7--PTP4A3 might be related to stage and DPH7--PTP4A3 might be related to grade and a poor prognosis. The biological functions of these fusion genes need to be further studied.
This work was supported by grants from the National Key R&D programme of China (No. YFC1303100 and No. YFC1303103).
Conflicts of interest
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Fusion genes; Endometrial cancer; Drug resistance; Prognosis
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