FAM83 family oncogenes are broadly involved in human cancers: an integrative multi-omics approach

Abstract

The development of novel targeted therapies for cancer treatment requires identification of reliable targets. FAM83 ('family with sequence similarity 83') family members A, B, and D were shown recently to have oncogenic potential. However, the overall oncogenic abilities of FAM83 family genes remain largely unknown. Here, we used a systematic and integrative genomics approach to investigate oncogenic properties of the entire FAM83 family members. We assessed transcriptional expression patterns of eight FAM83 family genes (FAM83A-H) across tumor types, the relationship between their expression and changes in DNA copy number, and the association with patient survival. By comparing the gene expression levels of FAM83 family members in cancers from 17 different tumor types with those in their corresponding normal tissues, we identified consistent upregulation of FAM83D and FAM83H across the majority of tumor types, which is largely driven by increased DNA copy number. Importantly, we found also that a higher expression level of a signature of FAM83 family members was associated with poor prognosis in a number of human cancers. In breast cancer, we found that alterations in FAM83 family genes correlated significantly with TP53 mutation, whereas significant, but inverse correlation was observed with PIK3CA and CDH1 (E-cadherin) mutations. We also identified that expression levels of 55 proteins were significantly associated with alterations in FAM83 family genes including a decrease in GATA3, ESR1, and PGR proteins in tumors with alterations in FAM83. Our results provide strong evidence for a critical role of FAM83 family genes in tumor development, with possible relevance for therapeutic target development.

Keywords: FAM83 family; copy number variation; gene mutation; multi-omics approach; oncogenes.

Figure 1

Gene expression levels of FAM83 family genes vary across normal human tissue types. Box plots of RPKM levels of FAM83 family genes across 53 different tissue types.

Figure 2

FAM83D and FAM83H are consistently overexpressed across human tumor types. Gene expression of FAM83 family genes across different tumor types. Increased or decreased gene expression (1.5‐fold; adjusted P < 0.05) is shown in orange and green, respectively.

Figure 3

DNA copy number of FAM83D and FAM83H is strongly correlated with gene expression. (A) Heatmap of the P‐values of the relationship between DNA copy number and gene expression (Kruskal–Wallis test; P < 0.01). Tumor type abbreviations: breast: breast invasive carcinoma; cesc: cervical squamous cell carcinoma and endocervical adenocarcinoma; ucec: uterine corpus endometrial carcinoma; skcm: skin cutaneous melanoma; coadread: colorectal adenocarcinoma; stad: stomach adenocarcinoma; luad: lung adenocarcinoma; hnsc: head‐and‐neck squamous cell carcinoma; kirc: kidney renal clear cell carcinoma; blca: urothelial bladder carcinoma; paad: pancreatic adenocarcinoma; prad: prostate adenocarcinoma; lihc: liver hepatocellular carcinoma; ov: ovarian serous cystadenocarcinoma; lusc: lung squamous cell carcinoma; lgg: low‐grade glioma; gbm: glioblastoma multiforme; kirp: kidney renal papillary cell carcinoma; pcpg: pheochromocytoma and paraganglioma; laml: acute myeloid leukemia; thca: thyroid carcinoma. (B–D) Box plot of the relationship between DNA copy number and gene expression for FAM83H in ovarian cancer (panel B; P = 1.77E‐19), prostate adenocarcinoma (panel B; P = 5.17E‐19), and breast cancer (panel C; P = 4.29E‐83). The kernel probability density of the data at different values is shown.

Figure 4

Increased expression of FAM83 family genes is associated with poor survival. (A) Heatmap of the P‐values for disease‐free survival for individual FAM83 family genes across 17 independent tumor data sets. Genes significantly associated with poor disease‐free survival when upregulated (P < 0.02) are shown in red, while genes significantly associated with poor disease‐free survival when downregulated (P < 0.02) are shown in blue. (B) For each tumor type, survival risk curves are shown; low and high risks are drawn in green and red, respectively. The P‐value represents the equality of survival curves based on a log‐rank test.

Figure 5

FAM83 family genes are frequently altered in breast cancer. (A) Spectrum of aberrations in FAM83 family genes in 960 human breast cancer samples. DNA copy number amplifications and/or gene expression upregulation are shown in red, DNA copy number loss and/or gene expression downregulation are shown in blue, and missense and truncating mutations are shown in green and black, respectively. (B) The percentage of breast cancer samples with TP53, PIK3CA, and CDH1 mutations in tumors with an alteration in at least one FAM83 family member (blue) and tumors without alteration in FAM83 genes (green). (C) Protein levels of CCNB1, GATA3, PGR, and ESR1 in breast cancer samples with an alteration in at least one FAM83 family member (blue) and samples without alteration in FAM83 genes (green).