Derivation and Validation of a Prognostic Model for Cancer Dependency Genes Based on CRISPR-Cas9 in Gastric Adenocarcinoma

Abstract

As a CRISPR-Cas9-based tool to help scientists to investigate gene functions, Cancer Dependency Map genes (CDMs) include an enormous series of loss-of-function screens based on genome-scale RNAi. These genes participate in regulating survival and growth of tumor cells, which suggests their potential as novel therapeutic targets for malignant tumors. By far, studies on the roles of CDMs in gastric adenocarcinoma (GA) are scarce and only a small fraction of CDMs have been investigated. In the present study, datasets of the differentially expressed genes (DEGs) were extracted from the TCGA-based (The Cancer Genome Atlas) GEPIA database, from which differentially expressed CDMs were determined. Functions and prognostic significance of these verified CDMs were evaluated using a series of bioinformatics methods. In all, 246 differentially expressed CDMs were determined, with 147 upregulated and 99 downregulated. Ten CDMs (ALG8, ATRIP, CCT6A, CFDP1, CINP, MED18, METTL1, ORC1, TANGO6, and PWP2) were identified to be prognosis-related and subsequently a prognosis model based on these ten CDMs was constructed. In comparison with that of patients with low risk in TCGA training, testing and GSE84437 cohort, overall survival (OS) of patients with high risk was significantly worse. It was then subsequently demonstrated that for this prognostic model, area under the ROC (receiver operating characteristic) curve was 0.771 and 0.697 for TCGA training and testing cohort respectively, justifying its reliability in predicting survival of GA patients. With the ten identified CDMs, we then constructed a nomogram to generate a clinically practical model. The regulatory networks and functions of the ten CDMs were then explored, the results of which demonstrated that as the gene significantly associated with survival of GA patients and Hazard ratio (HR), PWP2 promoted in-vitro invasion and migration of GA cell lines through the EMT signaling pathway. Therefore, in conclusion, the present study might help understand the prognostic significance and molecular functions of CDMs in GA.

Comprehensive Characterization of RNA Processing Factors in Gastric Cancer Identifies a Prognostic Signature for Predicting Clinical Outcomes and Therapeutic Responses

“…In contrast, genes with expression that related positively to the signature’s risk score were significantly enriched in the invasion, metastasis, and immune biological processes ( Figure 4 ). Among the 10 survival-related genes included in the signature, the risk-associated genes PWP2 and TGFB1 have been suggested to be associated with GC invasion and metastasis ( 50 , 51 ), and ZBTB7A , a protection-associated gene, plays a tumor-suppressive role in GC cells ( 52 ). METTL2B was found to be RNA methyltransferases and play important roles in tumorigenesis ( 53 ).…”

Expression and Clinical Significance of Origin Recognition Complex Family in Breast Cancer

“…The expression of ORCs in BC The ORCs was involved in the malignant progression of multiple tumors. Studies had shown that ORCs were differentially expressed in colorectal cancer, gastric cancer, and lung cancer and were related to biological behaviors such as cell proliferation, migration, and invasion [12][13][14][15][16]19 . Based on the Oncomine database, we also found that at least one of the ORCs was differentially expressed in colorectal cancer, gastric cancer, lung cancer and other tumors.…”

“…In recent decades, a large amount of evidence have shown that ORC is involved in other biological processes, such as heterochromatin formation, cytokinesis, viral replication, DNA damage repair, cognitive impairment and radiation in ammatory response [4][5][6][7][8][9] . ORCs are also differentially expressed in a number of tumors, such as gliomas 10 , endometrial cancer 11 , colon cancer [12][13][14] , gastric cancer 15,16 , liver cancer 17 , esophageal cancer 18 , and lung cancer 19 . They are implicated in diverse biological processes, including cell proliferation, migration, invasion, tumor stem cell maintenance, and chemotherapy resistance [11][12][13][19][20][21][22] .…”

“…They are implicated in diverse biological processes, including cell proliferation, migration, invasion, tumor stem cell maintenance, and chemotherapy resistance [11][12][13][19][20][21][22] . ORC1L, ORC5L and ORC6L have prognostic value in gastric cancer, liver cancer and colorectal cancer [14][15][16][17] . However, the expression levels and roles of ORCs in BC tumorigenesis remain to be elucidated.…”

Robust Glycogene-Based Prognostic Signature for Proficient Mismatch Repair Colorectal Adenocarcinoma

“…The other four genes of GlycoSig have not been investigated in the context of CRC; however, many studies have indicated their significance in other cancer types. Previous studies have shown that ALG8 could be a variate of prognostic model for gastric adenocarcinoma (51) and frequently amplified hotspot on 11q14.1 (ALG8) associated with significantly worse prognosis for breast cancer (52). The ALG6 single-nucleotide polymorphism (SNP) is a potential prognostic biomarker for cutaneous melanoma and is likely through modulating gene expression (53).…”