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From the Journals

Polymerase Mutations Shape Distinct Cancer Risks

Germline mutations in POLE and POLD1 are linked to variable cancer risks, with findings highlighting mutation-specific differences that refine tumor predisposition assessment.

Conexiant

Somatic and germline mutations affecting DNA polymerase proofreading functions are strongly linked to cancer development, tumor mutational burdens, and clinical outcomes, according to a comparative analysis of 249 hereditary cancer carriers and 360 proofreading-deficient tumors from public data sets.

Key Findings

Researchers identified 31 pathogenic missense variants clustered within or near the exonuclease domains of POLE and POLD1. These variants impair DNA proofreading activity, leading to hypermutated or ultramutated tumors with tumor mutational burdens often exceeding 100 mutations per megabase.

  • POLE-mutated tumors had a median burden of 160 mutations per megabase.

  • Tumors with both proofreading deficiency and mismatch repair deficiency exhibited even higher burdens.

  • Mutational signatures varied: POLE mutations were associated with SBS10a and SBS10b, while POLD1-driven hypermutation typically required a second somatic event or mismatch repair deficiency, indicating haploinsufficiency.

Cancer Associations

  • Endometrial cancer accounted for 75% of proofreading-deficient tumors in The Cancer Genome Atlas.

  • Colorectal cancer was the most frequent tumor among germline carriers (56%).

  • Endometrial cancer occurred more often in POLD1 carriers, while ovarian cancer was seen only in POLE carriers.

  • One-third of germline carriers developed multiple primary cancers.

  • Median ages of diagnosis were 42 years for colorectal cancer, 50 years for endometrial cancer, and 30 years for brain cancer.

Variant-Specific Risks

Certain POLE variants — including V411L, S297F, and A456P — were linked to aggressive hereditary presentations, with colorectal cancers diagnosed as early as 16 years.
Some early-onset cancers arose when a polymerase variant co-occurred with a mismatch repair gene variant, producing a phenotype resembling constitutional mismatch repair deficiency.

Tumor Histopathology

  • Most POLE-mutated endometrial cancers were endometrioid and classified as high grade.

  • All colorectal cancers were adenocarcinomas.

  • Most brain tumors were glioblastomas.

Limitations

The researchers noted several limitations:

  • Many hereditary case sequences were derived from formalin-fixed paraffin-embedded samples, which are lower quality than exome data from public cancer data sets.

  • Incomplete PPAP tumor data limited direct comparisons with sporadic cancers.

  • Small sample sizes for POLD1 variants restricted the strength of some associations.

The authors reported no conflicts of interest.

Source: Modern Pathology