Integrative expression quantitative trait locus-based analysis of colorectal cancer identified a functional...

Area of Science:

• Genetics
• Cancer Biology
• Molecular Epidemiology

Background:

• Single nucleotide polymorphisms (SNPs) are linked to colorectal cancer (CRC) risk, but known variants explain only a fraction of cases.
• Uncharacterized genetic determinants are crucial for understanding the full genetic basis of CRC.
• The Cancer Genome Atlas (TCGA) provides valuable multi-omics data for genetic association studies.

Purpose of the Study:

• To systematically identify novel genetic variants associated with colorectal cancer (CRC) risk using expression quantitative trait locus (eQTL) analysis.
• To validate the association of identified candidate SNPs with CRC risk in a large case-control study.
• To investigate the functional role of a significant SNP (rs27437) in the SLC22A5 gene and its impact on CRC development.

Main Methods:

• Expression quantitative trait locus (eQTL) analysis on The Cancer Genome Atlas (TCGA) multi-omics data for CRC.
• A two-stage case-control study involving 1528 CRC cases and 1528 controls.
• Dual-luciferase reporter assays to assess the functional impact of the rs27437 SNP on gene expression.

Main Results:

• Nine SNPs significantly affecting mRNA expression were identified through eQTL analysis.
• The SNP rs27437 in SLC22A5 showed a significant association with CRC risk across both study stages and the combined cohort (OR=1.31, P=1.97×10⁻⁶).
• The G allele of rs27437 was linked to reduced SLC22A5 mRNA expression and luciferase activity, and SLC22A5 levels were lower in CRC tumors.

Conclusions:

• The SNP rs27437 in SLC22A5 is a novel genetic risk factor for colorectal cancer.
• Reduced SLC22A5 expression, potentially mediated by the rs27437 G allele, may contribute to CRC pathogenesis.
• rs27437 in SLC22A5 holds potential as a biomarker for early detection and prevention of colorectal cancer.