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Meta-Analysis
. 2023 Sep 19;15(1):75.
doi: 10.1186/s13073-023-01229-9.

Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome

Jing Sun  1 , Jianhui Zhao  1 , Fangyuan Jiang  1 , Lijuan Wang  2 , Qian Xiao  3 , Fengyan Han  4 , Jie Chen  1 , Shuai Yuan  5 , Jingsun Wei  3 , Susanna C Larsson  5   6 , Honghe Zhang  4 , Malcolm G Dunlop  7   8 , Susan M Farrington  7 , Kefeng Ding #  3 , Evropi Theodoratou #  2   7 , Xue Li #  9   10
Affiliations
Meta-Analysis

Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome

Jing Sun et al. Genome Med. .

Abstract

Background: The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC).

Methods: Protein quantitative trait loci (pQTLs) were derived from seven published genome-wide association studies (GWASs) on plasma proteome, and summary-level data were extracted for 4853 circulating protein markers. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4957 cases and 304,197 controls), and the UK Biobank (9276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets.

Results: Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which four (GREM1, CLSTN3, CSF2RA, CD86) were prioritized with the most convincing evidence. These protein-coding genes are mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC.

Conclusions: This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC.

Keywords: Biomarker; Colorectal cancer; Drug target; Protein; Proteome-wide Mendelian randomization.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of the study design
Fig. 2
Fig. 2
Volcano plot showing results from proteome-wide Mendelian randomization (MR) in the discovery stage
Fig. 3
Fig. 3
Estimates of meta-analysis from discovery dataset and replication datasets for 13 proteome-wide identified proteins. Discovery dataset: CRC meta-GWASs. Replication datasets: CRC GWAS summary data from FinnGen and UK Biobank (UKBB)
Fig. 4
Fig. 4
Single-cell type expression in colon tumor tissue for the coding genes of proteins identified by proteome-wide Mendelian randomization. A A total of 11 cell clusters and six cell types were identified. B and C show the expression of protein coding genes in each cluster. D Six protein-coding genes had evidence of enrichment in a cell type at average Log2FC > 0.5 and FDR < 0.05 level
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