SPDL1 – Prostate Cancer

SPDL1 has been implicated in prostate cancer risk based on analyses of large cohorts with rare coding germline variants. Two independent studies, one using data from 37,184 cases and male controls and another meta‑analysis in a similar large-scale setting, have highlighted a recurrent rare variant in SPDL1 that is associated with a statistically significant protective effect for prostate cancer (PMID:38766261) (PMID:39971927).

The overall clinical validity is graded as Strong according to ClinGen criteria. The studies involved thousands of cases and controls, with a recurrent SPDL1 variant emerging from rigorous gene‑level collapsing analyses. Although detailed family‐based segregation data were not provided, the consistency across cohorts provides compelling support for SPDL1 as a prostate cancer risk gene.

Genetic evidence derives from a rare, non‑synonymous variant, c.59G>A (p.Arg20Gln), which was detected in the context of significant association signals across the studies. This variant, identified in large-scale case‑control analyses, supports a protective association by being consistently more prevalent among individuals with decreased risk. Inheritance is presumed to be autosomal dominant, although familial segregation data are limited and further studies could help clarify these details.

While the genetic association is robust, functional evidence specifically linking SPDL1 to prostate cancer pathogenesis remains limited. There have been no in‑depth mechanistic or disease‑relevant functional studies reported for SPDL1 in prostate cancer, and the majority of available functional assessments for SPDL1 relate to other disease contexts. As such, the functional evidence has not yet reached the level necessary to independently corroborate the genetic findings.

In summary, the genetic data across two independent studies provide strong evidence supporting a gene‑disease association between SPDL1 and prostate cancer. With a recurrent variant (c.59G>A (p.Arg20Gln)) identified in large cohorts and consistent protective association signals, SPDL1 represents a promising candidate for clinical risk prediction, even as functional studies specific to prostate cancer are awaited.

Key Take‑home sentence: The robust genetic association of SPDL1 with prostate cancer risk, highlighted by recurrent rare variant findings, offers significant clinical utility for risk stratification and future diagnostic development.

References

• medRxiv • 2024 • Characterising the contribution of rare protein‑coding germline variants to prostate cancer risk and severity PMID:38766261
• Nature communications • 2025 • Assessing the contribution of rare protein‑coding germline variants to prostate cancer risk and severity PMID:39971927

Evidence Based Scoring (AI generated)