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Identification of n...
Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome
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- Sun, Jing (author)
- Zhejiang Univ, Dept Big Data Hlth Sci, Sch Publ Hlth, Sch Med, Hangzhou, Zhejiang, Peoples R China.;Zhejiang Univ, Analyt Affiliated Hosp 2, Ctr Clin Big Data, Sch Med, Hangzhou, Zhejiang, Peoples R China.
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- Zhao, Jianhui (author)
- Zhejiang Univ, Dept Big Data Hlth Sci, Sch Publ Hlth, Sch Med, Hangzhou, Zhejiang, Peoples R China.;Zhejiang Univ, Analyt Affiliated Hosp 2, Ctr Clin Big Data, Sch Med, Hangzhou, Zhejiang, Peoples R China.
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- Jiang, Fangyuan (author)
- Zhejiang Univ, Dept Big Data Hlth Sci, Sch Publ Hlth, Sch Med, Hangzhou, Zhejiang, Peoples R China.;Zhejiang Univ, Analyt Affiliated Hosp 2, Ctr Clin Big Data, Sch Med, Hangzhou, Zhejiang, Peoples R China.
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- Wang, Lijuan (author)
- Univ Edinburgh, Usher Inst, Ctr Global Hlth, Edinburgh, Scotland.
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- Xiao, Qian (author)
- Zhejiang Univ, Affiliated Hosp 2, Colorectal Surg & Oncol, Key Lab Canc Prevent & Intervent,Minist Educ,Sch M, Hangzhou, Peoples R China.
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- Han, Fengyan (author)
- Zhejiang Univ, Sch Med, Womens Hosp, Dept Pathol, Hangzhou, Zhejiang, Peoples R China.
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- Chen, Jie (author)
- Zhejiang Univ, Dept Big Data Hlth Sci, Sch Publ Hlth, Sch Med, Hangzhou, Zhejiang, Peoples R China.;Zhejiang Univ, Analyt Affiliated Hosp 2, Ctr Clin Big Data, Sch Med, Hangzhou, Zhejiang, Peoples R China.
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- Yuan, Shuai (author)
- Karolinska Institutet
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- Wei, Jingsun (author)
- Zhejiang Univ, Affiliated Hosp 2, Colorectal Surg & Oncol, Key Lab Canc Prevent & Intervent,Minist Educ,Sch M, Hangzhou, Peoples R China.
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- Larsson, Susanna C. (author)
- Karolinska Institutet,Uppsala universitet,Medicinsk epidemiologi,Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden.
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- Zhang, Honghe (author)
- Zhejiang Univ, Sch Med, Womens Hosp, Dept Pathol, Hangzhou, Zhejiang, Peoples R China.
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- Dunlop, Malcolm G. (author)
- Univ Edinburgh, Med Res Council Inst Genet & Canc, Canc Res UK Edinburgh Ctr, Edinburgh, Scotland.;Univ Edinburgh, Inst Genet & Canc, Colon Canc Genet Grp, Edinburgh, Scotland.
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- Farrington, Susan M. (author)
- Univ Edinburgh, Med Res Council Inst Genet & Canc, Canc Res UK Edinburgh Ctr, Edinburgh, Scotland.
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- Ding, Kefeng (author)
- Zhejiang Univ, Affiliated Hosp 2, Colorectal Surg & Oncol, Key Lab Canc Prevent & Intervent,Minist Educ,Sch M, Hangzhou, Peoples R China.
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- Theodoratou, Evropi (author)
- Univ Edinburgh, Usher Inst, Ctr Global Hlth, Edinburgh, Scotland.;Univ Edinburgh, Med Res Council Inst Genet & Canc, Canc Res UK Edinburgh Ctr, Edinburgh, Scotland.
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- Li, Xue (author)
- Zhejiang Univ, Dept Big Data Hlth Sci, Sch Publ Hlth, Sch Med, Hangzhou, Zhejiang, Peoples R China.;Zhejiang Univ, Analyt Affiliated Hosp 2, Ctr Clin Big Data, Sch Med, Hangzhou, Zhejiang, Peoples R China.;Univ Edinburgh, Usher Inst, Ctr Global Hlth, Edinburgh, Scotland.
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Zhejiang Univ, Dept Big Data Hlth Sci, Sch Publ Hlth, Sch Med, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Analyt Affiliated Hosp 2, Ctr Clin Big Data, Sch Med, Hangzhou, Zhejiang, Peoples R China. Univ Edinburgh, Usher Inst, Ctr Global Hlth, Edinburgh, Scotland. (creator_code:org_t)
- BioMed Central (BMC), 2023
- 2023
- English.
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In: Genome Medicine. - : BioMed Central (BMC). - 1756-994X. ; 15:1
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- Colorectal cancer
- Protein
- Proteome-wide Mendelian randomization
- Biomarker
- Drug target
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Sun, Jing
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Zhao, Jianhui
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Jiang, Fangyuan
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Wang, Lijuan
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Xiao, Qian
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Han, Fengyan
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Chen, Jie
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Yuan, Shuai
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Wei, Jingsun
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Larsson, Susanna ...
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Zhang, Honghe
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Dunlop, Malcolm ...
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Farrington, Susa ...
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Ding, Kefeng
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Theodoratou, Evr ...
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Li, Xue
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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Genome Medicine
- By the university
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Uppsala University
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Karolinska Institutet