REV1: A novel biomarker and potential therapeutic target for various cancers

Abstract

Background: REV1 is a member of the translesion synthesis DNA polymerase Y family. It is an essential player in a variety of DNA replication activities, and perform major roles in the production of both spontaneous and DNA damage-induced mutations. This study aimed to explore the role of REV1 as a prognostic biomarker and its potential function regulating the sensitivity of anti-tumor drugs in various cancers. Methods: We analyzed the impact of REV1 gene alterations on patient prognosis and the impact of different REV1 single nucleotide polymorphisms (SNP) on protein structure and function using multiple online prediction servers. REV1 expression was assessed using data from Oncomine, TCGA, and TIMER database. The correlation between REV1 expression and patient prognosis was performed using the PrognoScan and Kaplan-Meier plotter databases. The IC50 values of anti-cancer drugs were downloaded from the Genomics of Drug Sensitivity in Cancer database and the correlation analyses between REV1 expression and each drug pathway's IC50 value in different tumor types were conducted. Results: Progression free survival was longer in REV1 gene altered group comparing to unaltered group [Median progression free survival (PFS), 107.80 vs. 60.89 months, p value = 7.062e-3]. REV1 SNP rs183737771 (F427L) was predicted to be deleterious SNP. REV1 expression differs in different tumour types. Low REV1 expression is associated with better prognosis in colorectal disease specific survival (DSS), disease-free survival (DFS), gastric overall survival (OS), post progression survival (PPS) and ovarian (OS, PPS) cancer while high REV1 expression is associated with better prognosis in lung [OS, relapse free survival (RFS), first progession (FP), PPS] and breast (DSS, RFS) cancer. In colon adenocarcinoma and rectum adenocarcinoma and lung adenocarcinoma, low expression of REV1 may suggest resistance to drugs in certain pathways. Conversely, high expression of REV1 in acute myeloid leukemia, brain lower grade glioma, small cell lung cancer and thyroid carcinoma may indicate resistance to drugs in certain pathways. Conclusion: REV1 plays different roles in different tumor types, drug susceptibility, and related biological events. REV1 expression is significantly correlated with different prognosis in colorectal, ovarian, lung, breast, and gastric cancer. REV1 expression can be used as predictive marker for various drugs of various pathways in different tumors.

Keywords: REV1; drug sensitivity; prognostic biomarker; single nucleotide polymorphism (SNP); translesion synthesis (TLS).

FIGURE 1

Molecular structure of REV1.

FIGURE 2

Copy number amplification and mutation status of REV1 (A) and corresponding progression free survival (B) in pan-cancer samples.

FIGURE 3

3D models of UmuC domain.

FIGURE 4

3D structure (A, C) and chemical structure changes (B) of position 427 on REV1 protein.

FIGURE 5

The expression level of REV1 in different types of tumor tissues and normal tissues. (A) Oncomine database. (B) TIMER database.

FIGURE 6

The immunohistochemistry staining images of REV1 in different types of tumor tissues and normal tissues [lung (A), stomach (B) and liver (C)].

FIGURE 7

The immunohistochemistry staining images of REV1 in different types of tumor tissues and normal tissues [urinary bladder (A), breast (B), kidney (C), prostate (D), thyroid (E), and endometrium (F)].

FIGURE 8

Correlation between REV1 expression and prognosis of various types of cancer [colorectal cancer (A, B), ovarian cancer (C, D), lung cancer (E–G), and breast cancer (H)] (PrognoScan database).

FIGURE 9

Correlation between REV1 expression and prognosis of various types of cancer [gastric cancer (A, B), ovarian cancer (C), lung cancer (D–F), rectum adenocarcinoma (G, H), and breast cancer (I)] (Kaplan-Meier Plotter database).

FIGURE 10

Correlation heatmap of REV1 expression and drug pathway’s IC50 in different tumors.