OR13C8 – Colorectal Cancer

OR13C8 has been identified as one of several candidate genes in a family with a high risk of colorectal cancer. In a study using whole exome sequencing, 12 novel non‑synonymous variants were found to co‐segregate in 5 affected members of a family with rectal and gastric cancer (PMID:26872740). Although the variant in OR13C8 was not singled out as high penetrance, its inclusion among the candidates prompts further scrutiny. The study design, focused on a single family, offers an initial genomic insight yet limits broad generalizability. Multiple candidate variants were reported, reflecting the complex genetic architecture of cancer predisposition. This introductory evidence establishes a preliminary link between OR13C8 and colorectal cancer risk.

The overall clinical validity of the association between OR13C8 and colorectal cancer is considered Limited. The evidence is based solely on segregation in one family, with 5 affected individuals showing co‑segregation of candidate variants (PMID:26872740). There is a lack of replication across unrelated probands or independent cohorts, which precludes stronger classification. Familial aggregation supports a potential contribution but does not reach the threshold required for a Strong or Definitive level of evidence. This limitation is compounded by the simultaneous identification of multiple candidate genes in the same family. As such, further case accumulation and independent validation are required.

Genetic evidence suggests an autosomal dominant mode of inheritance in the family under study. Specifically, segregation was observed in 5 affected relatives (PMID:26872740), yet no definitive coding variant for OR13C8 meeting ClinGen’s strict criteria is available from the dataset. The lack of a clearly attributable pathogenic variant in OR13C8 restricts the strength of the genetic evidence. While the candidate variant spectrum was assessed across 12 genes, detailed variant functional impact was not provided for OR13C8 specifically. Thus, the aggregate genetic data for OR13C8 remains limited in its scope and replicability. Overall, the genetic contribution of OR13C8 to colorectal cancer requires further investigation.

No substantial functional or experimental evidence has been reported that directly supports the pathogenicity of OR13C8 in colorectal cancer. The study did not include independent functional assays, animal or cellular models, or rescue experiments that demonstrate a clear disease mechanism. The absence of such evidence further weakens the overall support for a causal relationship. Without replication through validated functional studies, the mechanistic link between OR13C8 variants and the cancer phenotype remains speculative. This gap underscores the need for future experimental work aimed at elucidating the biological impact of OR13C8 alterations. Consequently, the current functional evidence is assessed as limited.

Conflicting evidence has not been explicitly documented, yet the presence of 11 additional candidate variants in the same family blurs the specific contribution of OR13C8. The study acknowledges the possibility of complex inheritance, where multiple variants might collectively influence cancer risk rather than a single high‐penetrance mutation driving the phenotype. Such a scenario complicates the interpretation and reduces the clarity of the association. Together, these factors introduce ambiguity in isolating the role of OR13C8 from other potential genetic contributors. Although no study has refuted the potential involvement of OR13C8, the context of multi‐gene involvement necessitates cautious interpretation. This further supports the Limited classification of the gene–disease association.

In summary, the integration of genetic segregation data and the paucity of functional evidence indicates that the association between OR13C8 and colorectal cancer is currently limited. The observation of co‑segregation in 5 affected family members supports a potential role in an autosomal dominant, complex inheritance model, but the lack of detailed variant data and independent functional validation restrains its clinical utility. The evidence is intriguing yet incomplete, and further studies are essential to validate OR13C8 as a definitive contributor to colorectal cancer risk. Key take‑home message: While preliminary findings suggest that OR13C8 may be involved in colorectal cancer predisposition, clinicians should interpret genetic findings with caution until additional evidence is available.

References

• BMC genetics • 2016 • Exome sequencing in one family with gastric- and rectal cancer PMID:26872740

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