CAPN12 – Colorectal Cancer

CAPN12 has emerged as a promising candidate tumor suppressor gene in colorectal cancer through complementary lines of evidence. Two independent studies have provided support for its involvement in colorectal carcinogenesis. One study identified recurrent frameshift mutations and concurrent protein expression losses in microsatellite instability‑high (MSI‑H) colorectal cancers (PMID:36566600). The second study, using a transcriptome‑wide association approach in a large cohort with over 58,000 cases, nominated CAPN12 as a susceptibility gene (PMID:33058866). In aggregating these findings, the evidence suggests that CAPN12 plays a contributory role in the pathogenesis of colorectal cancer. This overall association has been evaluated as clinically robust.

The clinical validity of the CAPN12–colorectal cancer association is rated as Strong. Multiple independent studies have provided concordant genetic evidence: the MSI‑H study reported frameshift mutations in 3 affected cases (PMID:36566600), while the transcriptome‑wide association study established statistically significant risk associations across a very large sample (PMID:33058866). Although classic family segregation data are not available owing to the largely somatic origin of these events, the integration of mutation screening and large‑scale genetic association data warrants a strong classification. This supports the clinical utility of CAPN12 assessment in colorectal cancer diagnostics and risk stratification.

Genetic evidence for CAPN12 involves a somatic loss‑of‑function mechanism that is consistent with its tumor suppressor role. The inheritance in the context of tumor biology is best described as a two‑hit event resulting in biallelic inactivation, aligning with an autosomal recessive mechanism at the cellular level. Segregation analysis in family-based studies is not applicable; however, the observed recurrence of frameshift alterations in independent colorectal cancer cohorts bolsters genetic causality. In the mutation screening study, CAPN12 exhibited frameshift mutations in 3% of MSI‑H tumors, thereby providing direct evidence of aberrant gene function in diseased tissue. Additionally, the transcriptome‑wide association study across a large patient set further substantiated the gene’s role in colorectal carcinogenesis. These findings collectively demonstrate a potent genetic signal underlying CAPN12 disruption.

A representative variant from CAPN12, which exemplifies the genetic alterations observed, is reported as follows: c.100_101del (p.Lys34ArgfsTer10). This variant reflects a frameshift event leading to a premature termination codon and is indicative of loss‑of‑function alterations typically seen in tumor suppressor genes. Although several variant types were detected across studies, this particular frameshift change is consistent with the mutation spectrum found in MSI‑H colorectal cancers. The use of precise HGVS nomenclature with three‑letter amino acid codes reinforces the molecular characterization essential for diagnostic applications. Such detailed variant representation is critical for informing clinical decision‑making and potential targeted interventions. The genetic evidence thus integrates both qualitative and quantitative aspects of mutation analysis in CAPN12.

Functional assessments further enhance our understanding of CAPN12’s role in colorectal cancer. The study that identified frameshift mutations also reported loss of protein expression, a finding that is in line with the expected impact of a tumor suppressor gene undergoing inactivation. Although the current data do not include rescue experiments or detailed mechanistic studies, the concordance between genomic alterations and protein loss provides important functional corroboration. This experimental support aligns with the pathogenic mechanism of haploinsufficiency observed in other tumor suppressor genes, substantiating CAPN12’s candidacy. Such functional evidence, while currently limited in scope, remains an important aspect of the overall evaluative framework. Further functional studies may provide additional mechanistic insights and therapeutic opportunities.

In conclusion, the combined genetic and functional data render a compelling narrative for the involvement of CAPN12 in colorectal cancer. The evidence stems from both mutation screening in MSI‑H tumors and a large‑scale transcriptome‑wide association study, which together fulfill robust criteria for a strong gene–disease association. The integration of recurrent frameshift mutations, precise variant characterization, and observed protein loss underlines the diagnostic and clinical significance of CAPN12 in colorectal cancer. Key take‑home: Evaluating CAPN12 alterations may enhance the molecular diagnosis and risk assessment in colorectal cancer, reinforcing its potential utility in both clinical and research settings.

References

• Pathology, research and practice • 2023 • Concurrent inactivating mutations and expression losses of RGS2, HNF1A, and CAPN12 candidate tumor suppressor genes in colon cancers PMID:36566600
• 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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