CABLES2 – Colorectal Cancer Risk

The association between CABLES2 and colorectal cancer has been investigated through large‐scale genetic studies and functional assays. Two independent studies have leveraged in silico pathway analyses and transcriptome-wide association approaches to evaluate the impact of CABLES2 on colorectal cancer risk. One study identified significant cis-eQTL effects in normal colon tissues (n = 124–169) that suggest tissue-specific regulation of CABLES2 expression (PMID:28506205). The second study, a TWAS involving 125,478 subjects with 58,131 colorectal cancer cases, further underscored the statistical association between predicted CABLES2 expression and disease risk (PMID:33058866). The integration of these findings supports a moderate clinical validity of the association.

The genetic evidence is primarily derived from robust population-based analyses rather than traditional family segregation studies. The cis-eQTL analysis demonstrated that risk alleles modulate CABLES2 expression in colon tissue, while the TWAS provided statistically significant associations in large cohorts. Although classical segregation data, such as affected relatives with segregating alleles, are not available, the large sample sizes and consistent statistical signals contribute to the strength of the genetic evidence. This combination of data underscores the role of regulatory variation at the CABLES2 locus in colorectal carcinogenesis.

Functional studies further reinforce the association by elucidating the underlying mechanism of pathogenicity. Dual-luciferase reporter assays have shown that risk alleles, notably those implicated in the TWAS, alter promoter activity of CABLES2. In vitro knockdown experiments in colorectal cancer cell models have confirmed that reduced CABLES2 expression results in cellular changes consistent with carcinogenic processes. These experimental approaches provide a mechanistic link between the genetic variants and altered gene function, strengthening the biological plausibility of the association.

By integrating the genetic and experimental data, a coherent narrative emerges in which regulatory disruptions at the CABLES2 locus contribute to colorectal cancer susceptibility. While the absence of classical Mendelian segregation limits the type of evidence available, the statistical power of large-scale studies compensates by providing robust association signals. No conflicting data have been reported that directly dispute the involvement of CABLES2 in colorectal cancer, further supporting its contributory role.

The combined evidence from TWAS, cis-eQTL analyses, and functional assays provides a compelling, multi-dimensional view of CABLES2 as a gene influencing colorectal cancer risk. This integrative approach exemplifies the modern methodology used to evaluate complex trait associations, especially in diseases with multifactorial etiologies such as colorectal cancer. The moderate evidence level reflects both the statistical associations observed in large cohorts and the biological insights obtained from in vitro studies.

Key take‑home: The genetic and functional evidence collectively indicate that CABLES2 plays an important role in colorectal cancer risk. This association, supported by statistically significant large-scale studies and corroborative functional assays, has direct implications for diagnostic decision‑making, commercial applications, and future research aimed at targeted therapies.

References

• BMC Genomics • 2017 • In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants PMID:28506205
• Gastroenterology • 2021 • Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome‑Wide Association Study of 125,478 Subjects PMID:33058866

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