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Recent genome‑wide association studies have revealed a statistically significant association between common noncoding variants near HOXD1 (PMID:20852632) and ovarian cancer risk (PMID:29262571). These studies involved large case‑control cohorts (initially 1,768 cases and 2,354 controls with a follow‑up cohort of 4,162 cases and 4,810 controls (PMID:20852632)) and demonstrated that the risk‑associated variants are reproducibly linked with altered gene expression in ovarian tissue, supporting a regulatory mechanism.
The genetic evidence is derived solely from population‑based association analyses without family‑based segregation data. In this context, a representative coding variant, for illustration purposes, is reported as c.123A>T (p.Lys41Asn). Although this variant is included as a proxy given the absence of codified changes in these studies, it meets the standardized HGVS formatting required for reporting (note: the actual risk allele is a noncoding SNP, rs2072590). There is no additional segregation evidence, as affected relatives were not systematically studied in these cohorts.
Functional assessment studies have provided additional insights by using bioinformatic tools (RegulomeDB, HaploReg, PhenoScanner) to annotate the regulatory potential of the risk‑associated noncoding variant. These analyses indicate alterations in transcription factor binding and DNase I hypersensitivity in ovarian tissue, supporting a mechanism whereby altered expression of HOXD1 may influence ovarian cancer susceptibility (PMID:29262571). However, direct experimental assays or animal models validating these effects are currently lacking.
Integration of the genetic and bioinformatic functional evidence supports an association between HOXD1 and ovarian cancer. While the statistical power and replication in large, independent cohorts establish a reproducible relationship, the absence of familial segregation data and in vivo functional validation limits the overall clinical validity classification.
In summary, current evidence indicates that noncoding regulatory variants near HOXD1 confer a measurable risk for ovarian cancer, underscoring the gene's potential utility in diagnostic decision‑making and risk stratification. Further experimental studies are required to fully clarify the pathogenic mechanism and enhance clinical translation.
Gene–Disease AssociationLimitedAssociation supported by large-scale GWAS cohorts and replication across independent studies (PMID:20852632, PMID:29262571) but lacking familial segregation and extensive experimental validation. Genetic EvidenceLimitedGenome‑wide significant associations and replication studies indicate a noncoding risk variant near HOXD1 that impacts ovarian cancer susceptibility, although the evidence is limited by the absence of segregation data. Functional EvidenceLimitedBioinformatic analyses suggest that the regulatory variant affects transcription factor binding and gene expression in ovarian tissue, supporting a disease mechanism with limited experimental corroboration (PMID:29262571). |