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CLDN18 is a key component of tight junctions and has recently been found to be aberrantly expressed in colorectal cancer. Emerging multi‑patient studies indicate that CLDN18 is upregulated in colorectal tumors, particularly in BRAF‑mutated cases (PMID:36975409). Although no rare pathogenic variants have been reported for CLDN18 in this context, its differential expression suggests that regulatory mechanisms may contribute to tumor biology. The observed overexpression aligns with altered tumor microenvironments that favor malignant progression. These findings, derived from large transcriptomic datasets, highlight the potential of CLDN18 as a biomarker in colorectal cancer. The evidence thus far justifies further investigation into its diagnostic and therapeutic utility.
The overall gene‑disease association is classified as Moderate according to ClinGen criteria. This designation reflects the integration of expression profiling data from sizable patient cohorts with robust functional insights. While traditional genetic evidence via rare variant detection and family segregation is absent (PMID:36975409), consistent upregulation across independent studies bolsters the association. The reproducibility of these findings and their correlation with clinical outcomes support a moderate level of association. Additional genetic studies, including deep sequencing in familial cases, are needed to elevate the confidence level. In summary, the available data sufficiently support a Moderate classification for clinical decision‑making.
Genetic evidence for CLDN18 in colorectal cancer remains limited as no specific deleterious variants have been identified. The current literature predominantly relies on expression analysis rather than direct mutation screening. This absence of reported coding changes or segregation analysis prevents the accumulation of traditional genetic evidence. Nonetheless, the recurrent upregulation observed in tumor samples from multiple independent cohorts lends indirect support to a role in disease etiology. The lack of variant‐level evidence is partially offset by the consistent transcriptomic signal detected in large-scale studies. Future sequencing efforts may uncover rare variants or somatic mutations that clarify its genetic contribution. Overall, the genetic evidence tier is therefore rated as Limited.
Functional studies, however, provide strong supportive evidence for the involvement of CLDN18 in colorectal cancer progression. One recent investigation demonstrated that the small protein encoded by LINC01547‑ORF interacts with CLDN18, reducing its ubiquitination and thereby enhancing its stability, which in turn modulates the FAK‑PI3K/AKT signaling pathway (PMID:39659940). In a complementary study from gastric cancer cells, CLDN18 expression was shown to be regulated by the PKC/MAPK/AP‑1 pathway, suggesting a conserved role of CLDN18 in gastrointestinal malignancies (PMID:18032479). These assays, including protein interaction and inhibition experiments, underscore the functional impact of CLDN18 on critical cell signaling cascades that govern proliferation and migration. The convergence of these functional data across related cancer types solidifies the mechanistic plausibility of CLDN18’s oncogenic role. Such insights advocate for the clinical relevance of targeting CLDN18 in therapeutic strategies.
Integrating the available evidence produces a coherent narrative: while direct genetic (variant‑based) evidence is currently limited, the repeated observation of CLDN18 upregulation in colorectal tumors and its proven functional effects on key oncogenic pathways support its role in colorectal cancer. The moderate association classification is derived from multi‑patient expression studies and is further strengthened by functional experiments demonstrating a direct impact on tumor cell behavior. Although additional studies are required to identify specific mutational events, the present data provide a strong rationale for the clinical evaluation of CLDN18 as a biomarker. This synthesis of genetic and functional evidence underscores CLDN18’s potential utility in diagnostic and therapeutic decision‑making. It also encourages future research to further delineate its role in colorectal oncogenesis.
Key take‑home: Despite limited direct genetic evidence, the robust functional data and reproducible overexpression of CLDN18 in colorectal cancer solidify its promise as a diagnostic biomarker and therapeutic target, warranting its inclusion in future clinical assessments and assay development.
Gene–Disease AssociationModerateUpregulation of CLDN18 across large colorectal cancer cohorts with supportive clinical correlations; however, lack of specific rare variants and segregation data limits the evidence. Genetic EvidenceLimitedNo clear pathogenic variants or familial segregation evidence have been reported, with data largely relying on transcriptomic observations. Functional EvidenceStrongRobust functional studies demonstrate that modulation of CLDN18 impacts key oncogenic pathways, including the FAK‑PI3K/AKT axis, supporting its biological role in colorectal cancer. |