CLCA4 and Colorectal Cancer

The association between CLCA4 and colorectal cancer is supported by multi‐patient studies that identified frameshift mutations and loss of protein expression in a subset of colorectal tumors, particularly those with high microsatellite instability (MSI-H) (PMID:32773719). This evidence underlines a potential tumor suppressor role for CLCA4 in regulating chloride transport, where its inactivation may contribute to the malignant transformation in the colorectal mucosa.

Genetic evidence from the study revealed that among 146 colorectal cancer samples, 12 out of 101 tumors with MSI-H showed CLCA4 frameshift mutations. Although no familial segregation was evaluated, this somatic mutational load in sporadic cases provides robust support for the gene’s involvement in colorectal tumorigenesis (PMID:32773719).

The variant spectrum includes loss‐of‐function events; one representative mutation is reported as c.772_790del (p.Ser258TrpfsTer39), which is indicative of a disruption in the normal protein product. This mutation, along with similar alterations, strongly supports a mechanism where CLCA4 inactivation is tied to cancer progression (PMID:32773719).

Functional assessment studies further demonstrated significant loss of CLCA4 protein expression in approximately 50% of colorectal cancers examined. These observations were corroborated by immunohistochemical analyses that showed reduced staining in tumors harboring the frameshift mutation relative to wild-type, aligning with the predicted loss of function (PMID:32773719).

The interplay of genetic mutations and subsequent functional deficits in CLCA4 provides a coherent narrative that reinforces its role as a putative tumor suppressor. The consistency across quantitative mutational evidence and qualitative protein expression studies contributes to a strong overall gene-disease association.

Additional integrated bioinformatics analysis from related studies supports these findings, although the strongest evidence arises from the direct assessment of mutation frequency and protein expression alterations in clinical samples (PMID:32462020).

Key take‑home sentence: The robust genetic and functional evidence substantiates that CLCA4 loss-of-function mutations are strongly associated with colorectal cancer pathogenesis, offering critical insights for diagnostic decision‑making and potential targeted interventions.

References

• Applied immunohistochemistry & molecular morphology : AIMM • 2020 • Frameshift Mutations and Loss of Expression of CLCA4 Gene are Frequent in Colorectal Cancers With Microsatellite Instability PMID:32773719
• BioMed Research International • 2020 • Identification and Verification of Core Genes in Colorectal Cancer PMID:32462020

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