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The association between STXBP4 and breast cancer is supported by multiple large‐scale studies that have fine‐mapped the 17q22 locus and identified common intronic variants strongly associated with breast cancer risk (PMID:27600471). High resolution analyses in >89,000 individuals have revealed a cluster of 28 highly correlated variants within a 53 Kb region of STXBP4. These findings affirm that genetic variation in this locus contributes to disease susceptibility.
Clinical validity is reinforced by evidence from independent multi‐patient and transcriptome‐wide association studies. One study demonstrated that the lead SNP (rs2787486) was significantly associated with decreased risk (OR = 0.92; PMID:27600471), while a separate TWAS specifically linked STXBP4 with estrogen receptor positive breast cancer (PMID:32115800). Additionally, allelic expression analyses further substantiated the regulatory effects of risk alleles on STXBP4 transcript levels (PMID:35772352).
Genetic evidence supporting this association is robust. The fine‐mapping study not only identified a cluster of candidate variants but also bolstered these findings through computational ranking and eQTL analyses. Although no specific coding variant in HGVS nomenclature was directly reported, the constellation of common intronic variants serves as a proxy for the gene’s risk alleles, demonstrating significant statistical associations in large-scale cohorts (PMID:28422318).
Functional evidence, while emerging, further supports the pathogenic role of STXBP4. Experimental studies in cellular models have demonstrated that STXBP4 regulates key cellular processes, such as APC/C-mediated turnover of p63, an effect that is pertinent to oncogenesis (PMID:29735662). Although these functional assays were primarily conducted in the context of squamous cell carcinoma, they provide mechanistic insight into how dysregulation of STXBP4 may contribute to tumorigenesis in different tissues, including the breast.
There is no directly conflicting evidence undermining the genetic association with breast cancer. Differences in tissue specificity among functional studies are acknowledged, but the genetic data across multiple independent cohorts consistently support the relevance of STXBP4 variation in breast cancer risk. Together, these data warrant a strong clinical validity classification.
In summary, the integrated genetic and experimental evidence supports a strong association between STXBP4 and breast cancer. Given the convergence of fine-mapping, TWAS, and allelic expression data, STXBP4 emerges as an important candidate for breast cancer risk stratification. Key take‐home message: The STXBP4 locus exhibits strong clinical utility as a genetic risk factor for breast cancer, meriting further clinical and translational exploration.
Gene–Disease AssociationStrongMultiple independent studies in large cohorts (>89,000 participants [PMID:27600471]) and TWAS analyses ([PMID:32115800]) support a robust association between STXBP4 and breast cancer risk. Genetic EvidenceStrongFine mapping identified 28 highly correlated variants within STXBP4; additional allelic expression and TWAS studies further substantiate the association ([PMID:35772352], [PMID:28422318]). Functional EvidenceModerateFunctional studies demonstrate that STXBP4 influences key oncogenic pathways, such as p63 turnover, aligning with cancer biology, although these studies are primarily in squamous cell contexts ([PMID:29735662]). |