Identification of Prognostic and Therapeutic Biomarkers among FAM83 Family Members for Pancreatic Ductal Adenocarcinoma

Abstract

Family with sequence similarity 83 (FAM83) members were shown recently to have oncogenic effect in a variety of cancer types, but the biological roles and prognostic value of FAM83 family in pancreatic ductal adenocarcinoma remain unknown. In the current study, the clinical significance and molecular function of the FAM83 family were assessed by multiple bioinformatics analysis. Besides, potential associations between differentially expressed genes (DEGs) of FAM83 family and antitumor immunity were evaluated using TIMER and TISIDB analyses. As the results show, FAM83A, FAM83D, FAM83E, and FAM83H were significantly upregulated in PDAC and were identified as DEGs. Higher expression of FAM83A, FAM83B, FAM83D, FAM83E, and FAM83H were associated with advanced tumor stage or worse patient prognosis. Importantly, the overexpression of DEGs was found to be significantly correlated with activated KRAS and loss of SMAD4, which are important drivers for PDAC. Further, FAM83A, FAM83D, and FAM83H were associated with CD8⁺ T cell, Gamma Delta T cell, and CD4⁺ T cell infiltration in PDAC and FAM83H was found closely correlated with some immunomodulators including immunoinhibitors, immunostimulators, and MHC molecules. In conclusion, FAM83A, FAM83D, FAM83E, and FAM83H have significant prognostic value in PDAC and they may play important roles in regulating tumor progression and the immune cell infiltration.

Figure 1

Transcriptional levels of FAM83 family members in pancreatic ductal adenocarcinoma (PDAC). (a) Oncomine dataset analysis showed the numbers of datasets with significant transcriptional upregulated expression (red) or downregulated expression (blue). (b) GEPIA dataset analysis validated increased FAM83A, FAM83D, FAM83E, and FAM83H expression in PDAC tumor. The fold change cutoff was 1.5, and the p value cutoff was 0.05. Transcriptional expression levels of FAM83 family members in PDAC are delineated with red highlights.

Figure 2

Relative expression, coexpression, genetic alteration, and neighbor gene network of the FAM83 family in pancreatic ductal adenocarcinoma (PDAC): (a) relative level of FAM83 family members in PDAC; (b) coexpression of FAM83 family members in PDAC; (c) summary of alterations in FAM83 family members in PDAC; (d) neighbor gene network of FAM83 family members.

Figure 3

Correlation between FAM83 family members and tumor pathological stage of pancreatic ductal adenocarcinoma (PDAC) patients.

Figure 4

Prognostic value of FAM83 family members in pancreatic ductal adenocarcinoma (PDAC) patients in the overall survival curve (a) and disease-free survival curve (b).

Figure 5

Gene Ontology (GO) enrichment analysis of differentially expressed FAM83 family members and neighboring genes in pancreatic ductal adenocarcinoma (PDAC): (a) GO enrichment analysis of FAM83A; (b) GO enrichment analysis of FAM83D; (c) GO enrichment analysis of FAM83E; (d) GO enrichment analysis of FAM83H. Color: enriched p value.

Figure 6

Correlation between expression levels of differentially expressed FAM83 family members with important driver genes of pancreatic ductal adenocarcinoma (PDAC) including KRAS (a) and SMAD4 (b).

Figure 7

Association between the different expressions of FAM83 family with T cell infiltration levels in pancreatic ductal adenocarcinoma (PDAC): (a) R between the expression of FAM83A, D, E, and H with T cell infiltration levels including CD8+ T cell, Gamma Delta T cell, follicular helper T cell, and CD4⁺ T cell in PDAC. (b-d) Spearman's correlation between the expression of FAM83A, E, and H with CD8⁺ T cell (b), Gamma Delta T cell (c), and naive CD4⁺ T cell (d) infiltration levels. Red and blue cells showed positive and negative correlations, respectively. The intensity of color was proportional to the strength of the correlations.

Figure 8

Correlations of FAM83H with tumor-infiltrating lymphocytes (TILs) and immunomodulators: (a) correlations between TILs and FAM83H expression; (B) top 4 TILs with the greatest negative Spearman correlation with FAM83H; (c) correlations between immunoinhibitors and FAM83H expression; (d) top 3 immunoinhibitors with the greatest positive Spearman correlation with FAM83H; (e) correlations between immunostimulators and FAM83H expression; (f) top 4 immunostimulators with the greatest negative Spearman correlation with FAM83H; (g) correlations between MHC molecules and FAM83H expression; (h) top 4 MHC molecules with the greatest negative Spearman correlation with FAM83H. Red and blue cells showed positive and negative correlations, respectively. The intensity of color was proportional to the strength of the correlations.