SGO1 and Gastric Cancer

SGO1 is emerging as a gene of interest in gastric cancer, with recent studies highlighting the presence of recurrent frameshift variants. Comprehensive genomic analyses in gastric tumors, particularly in those with microsatellite instability (MSI) and microsatellite stable cases, indicate that SGO1 mutations are not strictly confined to a specific MSI status (PMID:32817265). The association has been supported by multi‐patient studies that found a notable frequency of these variants, suggesting that alterations in SGO1 may contribute to the pathogenesis of gastric cancer. As a putative tumor suppressor, SGO1 plays a key role in chromatid cohesion and checkpoint control during mitosis. The genetic data, combined with functional insights, provide an integrated view that supports its disease involvement. This association is important for both diagnostic decision‑making and the development of novel management strategies for gastric cancer.

The clinical validity of the SGO1–gastric cancer association is evaluated as Strong according to the ClinGen framework. In one study, a frameshift variant (c.973del (p.Met325CysfsTer28)) was identified in 16 out of 45 evaluable gastric cancer cases (PMID:32817265). Such a frequency, observed across a broad patient cohort, combined with supportive evidence from related studies, bolsters the overall gene–disease association. Although segregation analysis in affected relatives has not been extensively explored in these somatic contexts, the repeated finding of this variant strengthens its clinical significance. Multi‐patient data and recurrent mutation events highlight the potential impact of this genetic alteration on tumor biology. These findings are crucial in guiding both commercial testing platforms and future research publication efforts.

Genetic evidence further reinforces this association, with the recurrent detection of the frameshift variant c.973del (p.Met325CysfsTer28) in gastric cancer samples. This variant, detected in a significant subset of cases, underscores the importance of disruptions in the coding sequence of SGO1. The mutation is conferred by a single nucleotide deletion leading to a premature termination codon, which likely results in loss of normal protein function. The presence of this variant in both MSI‐high and microsatellite stable tumors suggests that its occurrence may be independent of the traditional MSI pathway. Such a variant pattern is consistent with a tumor suppressor role, where LoF (loss‑of‑function) mutations contribute to neoplastic transformation. These insights are supported by robust case‐report data and multi‑patient series, making the genetic evidence compelling.

Functional studies, while not exclusively performed in gastric tissues, provide important context regarding the role of SGO1 in maintaining genomic stability. Experimental assessments have established that SGO1 is critical for proper chromatid segregation and kinetochore function, and its dysregulation can easily contribute to aneuploidy—a hallmark of cancer. In vitro assays and cellular models suggest that impaired SGO1 function due to frameshift mutations disrupts the cohesin complex and, consequently, compromises the mitotic checkpoint. These mechanistic insights align well with the observed genetic alterations in gastric cancer and indicate that the loss of normal SGO1 function may promote tumorigenesis. Although direct functional assays in gastric models remain limited, the available experimental evidence supports a moderating role of functional disturbance in the overall pathogenic framework. Thus, the functional evidence for the association is rated as Moderate.

There is, however, evidence that introduces complexity to this association. The gastric cancer study noted that the c.973del variant in SGO1 is observed in both MSI‐high and microsatellite stable tumors, suggesting that the variant alone does not strictly define an MSI phenotype. This variability indicates that additional genetic or environmental modifiers could influence the disease course in these patients. Moreover, while the recurrence and functional implications of the SGO1 mutation are evident, alternative pathogenic pathways in gastric cancer may further confound the attribution of causality solely to SGO1 alterations. Such nuances underscore the importance of integrating multiple lines of evidence when considering its clinical utility. Despite these complexities, the genetic and experimental data remain largely supportive of the association, with no studies directly refuting the overall link between SGO1 disruption and gastric cancer pathogenesis.

In summary, the integrated evidence from case series and functional studies reinforces a strong gene–disease association between SGO1 and gastric cancer. The recurrent frameshift mutation c.973del (p.Met325CysfsTer28) provides a robust genetic marker, while the essential role of SGO1 in chromosomal stability offers a plausible mechanistic explanation. This association is not only pivotal for the understanding of gastric tumorigenesis but also holds significant promise for enhancing diagnostic precision and informing targeted therapeutic strategies. Key take‑home: SGO1 mutational analysis in gastric cancer can serve as a valuable diagnostic and prognostic tool, facilitating personalized treatment approaches.

References

• Journal of clinical pathology • 2020 • Microsatellite frameshift variants in SGO1 of gastric cancer are not always associated with MSI status PMID:32817265
• Human pathology • 2013 • Frameshift mutations of chromosome cohesion‑related genes SGOL1 and PDS5B in gastric and colorectal cancers with high microsatellite instability PMID:23850494

Evidence Based Scoring (AI generated)