PCOLCE2 and Colorectal Cancer

In a recent exome sequencing study investigating a family with a dominant cancer syndrome, PCOLCE2 (HGNC:8739) emerged among 12 novel non‑synonymous variants shared by 5 affected members (PMID:26872740). The study focused on families with a high risk of rectal and gastric cancer, with colorectal cancer being a key component of the clinical presentation. Although multiple candidate genes were identified, the involvement of PCOLCE2 remains of particular interest given its potential role in extracellular matrix interactions. The genetic data, however, are limited by the fact that multiple variants were reported simultaneously, making it challenging to definitively assign causality to PCOLCE2. The observed segregation in a single family is intriguing but does not provide strong statistical power. Further studies are necessary to clarify the gene’s role in cancer predisposition.

The inheritance pattern in the family was noted as autosomal dominant, which is consistent with the observed segregation of variants. In this context, five affected individuals shared the candidate variants, underscoring a possible dominant effect and supporting the involvement of PCOLCE2 in colorectal cancer risk. Although the family-based genetic evidence is promising, the overall case-level data are limited and warrant caution when interpreting the clinical relevance of PCOLCE2 for colorectal cancer. The complexity of the inheritance pattern, likely influenced by additional genetic factors, further complicates the picture. This scenario is not uncommon in familial cancer studies where multiple candidate loci are identified. Consolidation of these findings in larger cohorts will be essential.

From a genetic evidence standpoint, the association of PCOLCE2 with colorectal cancer is considered limited. The study reported 12 candidate variants in a single family, and while segregation analysis indicated that all affected members carried the variants, the presence of multiple genes under consideration dilutes the specific evidence for PCOLCE2. No variant specific to PCOLCE2 could be uniquely isolated from the family data, thereby limiting its individual contribution. With only one family evaluated, the statistical weight of the evidence does not meet the threshold for stronger classifications. Nonetheless, the detailed exome sequencing work provides a valuable starting point for future research. Large-scale case‐control studies are needed to strengthen or refute the gene–disease association.

Complementary functional assessments have been conducted for PCOLCE2, albeit in a different disease context. A separate investigation studied its role in adipocyte SR-BI-mediated HDL uptake in the context of atherosclerosis (PMID:34551590). These experimental studies demonstrated that PCOLCE2, through its extracellular matrix interactions, modulates SR-BI expression and function. However, while these data underscore a functional role for PCOLCE2 in lipid metabolism and cellular signaling, they do not directly establish its pathogenic mechanism in colorectal cancer. The functional evidence thus provides limited supportive data, emphasizing the need to directly assess its role in colorectal tumorigenesis. Overall, bridging experimental insights with clinical observations remains a priority.

Integrating the genetic and functional findings, the overall clinical validity for a role of PCOLCE2 in colorectal cancer remains limited. The case-level evidence provides an initial association in a single family exhibiting autosomal dominant inheritance, but the lack of more unequivocal functional and segregation data precludes a higher classification. Additional patient cohorts and experimental studies specific to the colorectal cancer pathway will be essential to verify these preliminary findings. Despite these limitations, the identified association has potential clinical utility if further validated. The data encourage continued investigation into the role of extracellular matrix proteins in cancer predisposition. Future research could also consider the possibility of complex inheritance models involving multiple genes.

Key take‑home sentence: Although current evidence for PCOLCE2 in colorectal cancer is limited, its identification in familial studies highlights a potential role warranting further investigation, which may ultimately enhance diagnostic precision and inform targeted therapy.

References

• BMC Genetics • 2016 • Exome sequencing in one family with gastric- and rectal cancer PMID:26872740
• Arteriosclerosis, Thrombosis, and Vascular Biology • 2021 • Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI-Mediated High-Density Lipoprotein Uptake PMID:34551590

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