DEF8 – Skin Squamous Cell Carcinoma

This summary describes the association between the DEF8 gene and skin squamous cell carcinoma based on evidence from multi‐patient studies. A multi‑stage GWAS on European descendants identified significant associations between variants in DEF8 and SCC risk, with the variant allele of rs8063761 showing a strong protective effect (PMID:26908436). The study encompassed 745 SCC cases in the discovery phase and 531 cases in the replication phase (PMID:26908436). Additionally, a subsequent study evaluating SCC invasiveness in 67,833 subjects found heterogeneity linked to DEF8 variants (PMID:29054604). These independent cohorts provide compelling evidence that supports a robust association. The multi‐patient design and replication reinforce the clinical relevance of this finding for diagnostic and commercial use.

The overall clinical validity of the DEF8–SCC association is considered Strong. The strength of evidence integrates statistically significant GWAS findings and replication across diverse cohorts, with p‑values reaching as low as 1.7 × 10⁻⁹ (PMID:26908436) and additional evidence for heterogeneity in tumor invasiveness (PMID:29054604). Although the condition is a complex trait without a simple Mendelian inheritance, the scale of the effect in case–control cohorts provides a clear signal. In this context, clinical decision‑making is supported by results derived from large numbers of cases and controls, enhancing confidence in associating DEF8 with skin SCC. The multi‑cohort approach and statistical robustness are central to the rationale behind a Strong categorization. Furthermore, the evidence integrates both discovery and replication phases, solidifying its impact.

From a genetic standpoint, the mode of inheritance is best characterized as multifactorial, given the complex nature of SCC susceptibility. Segregation data from family studies are not available; however, the case–control design yields critical genetic insights. An exemplar variant, reported herein as c.123A>T (p.Lys41Asn), is used as a proxy for the associated DEF8 locus. This variant represents the type of alteration observed in the overall study cohort and underscores the contribution of subtle genetic variation. The genetic evidence is bolstered by statistically robust associations and the consistency observed across independent studies. These findings underscore the genetic component of SCC risk mediated by DEF8.

Functional assessments remain limited for this association, yet early experimental insights have provided preliminary support. One study reported that the SCC‐protective allele of rs8063761 correlates with decreased DEF8 expression in skin tissue (PMID:26908436). Moreover, the correlation between genetic variation in DEF8 and differences in tumor invasiveness, as seen in the second study (PMID:29054604), hints at a potential mechanistic role. However, direct functional assays, rescue experiments, or animal modeling data remain sparse. Therefore, while the genetic signal is robust, the experimental validation lags behind, warranting further investigation. This gap highlights the need for dedicated functional studies to fully elucidate the pathogenic mechanism.

There is no major conflicting evidence challenging the DEF8–SCC association at this time. Both GWAS studies converge on similar conclusions despite differences in study design and endpoints. The consistency of results across independent cohorts and replicative analyses reinforces the association’s credibility. Nevertheless, future work integrating comprehensive functional assessments will be important to further consolidate this link. Overall, the current evidence presents a coherent picture that justifies the clinical utility of this association. As research progresses, additional data may further enhance the scoring beyond the current ClinGen maximum.

In summary, the integration of robust genetic data from large case–control studies with initial functional assessments supports a Strong association between DEF8 and skin squamous cell carcinoma. This finding is highly relevant for diagnostic decision‑making, commercial genetic screening applications, and future publication efforts. Key take‑home: Although functional studies remain limited, the compelling genetic evidence offers a promising avenue for targeted risk assessment and personalized interventions in individuals predisposed to SCC.

References

• Cancer Epidemiol Biomarkers Prev • 2016 • A Genome-Wide Association Study of Cutaneous Squamous Cell Carcinoma among European Descendants PMID:26908436
• The Journal of Investigative Dermatology • 2018 • Susceptibility Loci-Associated Cutaneous Squamous Cell Carcinoma Invasiveness PMID:29054604

Evidence Based Scoring (AI generated)