POLD2
Overview
POLD2 encodes the accessory subunit of DNA polymerase delta, a replicative DNA polymerase with roles in lagging-strand synthesis and DNA repair. In urothelial carcinoma, POLD2 is implicated in cellular cisplatin response; mutations in POLD2 were identified as private to the pre-chemotherapy clone in a rapid-autopsy case study, suggesting selective elimination of POLD2-altered cells by platinum-based chemotherapy.
Alterations observed in the corpus
- Mutation present in the untreated TURBT primary of patient WCM117 (urothelial carcinoma rapid-autopsy case, 12 samples across 8 anatomical sites) but absent from all post-chemotherapy metastatic lesions; interpreted as private to the clone eradicated by gemcitabine–cisplatin, alongside FOXP1, FGFR4, TRRAP, and EGFR; authors note POLD2 is implicated in cellular cisplatin response PMID:27749842
Cancer types (linked)
- BLCA — identified in the evolutionary analysis of urothelial carcinoma under platinum-based chemotherapy pressure; 32-patient WES cohort (72 tumors) from Weill Cornell Medicine enriched for advanced/metastatic disease PMID:27749842
Co-occurrence and mutual exclusivity
- POLD2 mutation was private to the pre-chemotherapy clone; its absence post-chemotherapy is consistent with the broader ATM/RB1/FANCC alteration signature (present in 73.3% of pre-chemotherapy vs 37.9% of post-chemotherapy tumors, p=0.05) that marks cisplatin-sensitive clones PMID:27749842
Therapeutic relevance
- POLD2 mutation status may serve as a candidate biomarker of cisplatin sensitivity in urothelial carcinoma; its selective depletion post-cisplatin + gemcitabine therapy supports this hypothesis, though functional validation is lacking PMID:27749842
Open questions
- The role of POLD2 mutations in mediating cisplatin sensitivity is inferred from clonal dynamics in a single patient (WCM117); functional studies in UC models are needed to confirm gain- or loss-of-function and mechanism PMID:27749842
Sources
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