Beyond proofreading: POLD1 mutations as dynamic orchestrators of genomic instability and immune evasion in cancer

Area of Science:

• Genomic stability and cancer biology
• Molecular mechanisms of DNA replication and repair
• Cancer immunotherapy and biomarkers

Background:

• DNA polymerase delta (Pol δ), encoded by POLD1, is crucial for DNA replication fidelity and repair via its proofreading exonuclease domain.
• Mutations in POLD1, especially in the exonuclease domain, lead to genomic instability and a hypermutated cancer phenotype.
• These mutations are associated with polymerase proofreading-associated polyposis (PPAP) and impact cancer development.

Purpose of the Study:

• To review the diverse roles of POLD1 mutations in cancer, including tumorigenesis and immunotherapy.
• To investigate the impact of POLD1 mutations on tumor immunogenicity and response to immune checkpoint inhibitors (ICIs).
• To highlight POLD1 mutations as potential biomarkers for immunotherapy in previously resistant cancer types.

Main Methods:

• Literature review integrating structural, mechanistic, and clinical data on POLD1 mutations.
• Analysis of POLD1 mutation-associated mutational signatures and their effect on tumor mutation burden.
• Evaluation of the relationship between POLD1 mutations, microsatellite stability (MSS), and ICI efficacy.

Main Results:

• POLD1 mutations disrupt DNA proofreading, driving genomic instability and cancer.
• Unexpectedly, POLD1 mutations enhance immunogenicity in microsatellite-stable (MSS) tumors.
• These mutations increase tumor mutation burden and create distinct mutational signatures (e.g., SBS10d), sensitizing MSS tumors to ICIs.

Conclusions:

• POLD1 mutations are significant drivers of cancer progression and genomic instability.
• POLD1 mutations represent a novel predictive biomarker for immunotherapy response, particularly in MSS tumors.
• Understanding POLD1 mutation roles redefines therapeutic strategies and expands precision oncology possibilities.