SPOP – Prostate Cancer

In a single multiplex family with early-onset prostate cancer, a novel germline SPOP missense variant, c.887A>T (p.Asn296Ile), completely segregates with disease status, implicating SPOP as a candidate predisposition gene (PMID:24796539). Although this represents only one pedigree, subsequent large exome sequencing efforts have demonstrated recurrent somatic SPOP mutations in 6–15% of sporadic prostate tumors, defining a distinct molecular subtype mutually exclusive with ETS rearrangements (PMID:22610119).

Functional studies reveal that prostate cancer–associated SPOP mutants, including p.Phe133Val and p.Gln165Pro, impair ubiquitin-mediated degradation of key substrates such as Caprin1, enhancing stress granule assembly and conferring resistance to docetaxel in cell and xenograft models (PMID:31771591). These mutants also disrupt DNA–protein cross-link repair by misregulating topoisomerase 2A turnover, promoting genomic instability and influencing therapeutic response. Key take-home: SPOP mutation testing refines molecular subclassification of prostate cancer and may guide personalized therapy.

References

• The Prostate • 2014 • Identification of a novel germline SPOP mutation in a family with hereditary prostate cancer. PMID:24796539
• Nature Genetics • 2012 • Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. PMID:22610119
• Molecular Cancer • 2019 • Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly. PMID:31771591

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