Five genes identified as prognostic markers for colorectal cancer through the integration of genome-wide association study and expression quantitative trait loci data

Abstract

Background: Colorectal cancer (CRC) is a prominent form of cancer globally, ranking second in terms of prevalence and serving as a leading cause of cancer-related deaths, but the underlying biological interpretation remains largely unknown. Methods: We used the summary data-based Mendelian randomization method to integrate CRC genome-wide association studies (n_case = 7062; n_control = 195,745) and expression quantitative trait loci summary data in peripheral whole blood (Consortium for Architecture of Gene Expression: n = 2765; Genotype-Tissue Expression [v8]: n = 755) and colon tissue (colon-transverse: n = 406; colon-sigmoid: n = 373) and identified related genes. Results: Genes ABTB1, CYP21A2, NLRP1, PHKG1 and PIP5K1C have emerged as significant prognostic markers for CRC patient survival. Functional analysis revealed their involvement in cancer cell migration and invasion mechanisms, providing valuable insights for the development of future anti-CRC drugs. Conclusion: We successfully identified five CRC risk genes, providing new insights and research directions for the effective mechanisms of CRC.

Summary points

• The primary objective of our study was to detect functional genes and regulatory elements in colorectal cancer (CRC) by combining genome-wide association study summary data with expression quantitative trait loci data.

• Through the utilization of the summary data-based Mendelian randomization method, we successfully integrated CRC genome-wide association study and expression quantitative trait loci datasets, resulting in the identification of 135 risk genes associated with CRC.

• Comprehensive Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that these 135 risk genes are significantly enriched in regulatory pathways crucial for cancer cell growth, metabolic processes and immune response.

• By combining data from colon adenocarcinoma and rectum adenocarcinoma cohorts within The Cancer Genome Atlas database, we discovered that among the 135 risk genes, ABTB1, CYP21A2, NLRP1, PHKG1 and PIP5K1C are strongly associated with the survival outcomes of CRC patients.

• Notably, the CYP21A2 gene exhibited a positive correlation with pathways involved in the proliferation and migration of CRC, underscoring its potential role as a susceptibility gene and a promising target for clinical intervention in CRC.

• These results provide important insights into the molecular mechanisms of CRC genomics and provide potential targets for treatment.

Keywords: :

• colorectal cancer
• eQTL
• genome-wide association studies
• risk gene
• summary data-based Mendelian randomization

Author contributions

X Qiu designed the study. C Zhang and W Huang finished the main work and wrote the manuscript. W Niu and H Yang revised and polished the manuscript. W Niu and Y Zheng performed the statistical analysis of the data. All authors reviewed the manuscript.

Financial disclosure

This work was supported by the Shanghai ‘Rising Stars of Medical Talent’ Youth Development Clinical Pharmacist Program (No. 2018-1), Shanghai Science and Technology Innovation Program 2019 Key Project in Soft Science Research Field (No. 19692107000) and the 2019 Key Clinical Program of Clinical Pharmacy (No. 451 shslczdzk06502). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The data from genome-wide association study and genotype-tissue expression databases are available for free to the public, and this study strictly followed access policies and publication guidelines. I confirm that all the research meets the ethical guidelines, including adherence to the legal requirements of the study country.

Acknowledgments

We thank all the participants of this study for their contributions.

Additional information

Funding

This work was supported by the Shanghai ‘Rising Stars of Medical Talent’ Youth Development Clinical Pharmacist Program (No. 2018-1), Shanghai Science and Technology Innovation Program 2019 Key Project in Soft Science Research Field (No. 19692107000) and the 2019 Key Clinical Program of Clinical Pharmacy (No. 451 shslczdzk06502). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.