Background and objectives
DNA polymerase A epsilon catalytic subunit (POLE) gene plays a key role in DNA repair and chromosomal replication. Mutations in POLE gene have been linked to cancer, particularly colorectal carcinoma (CRC). However, the genomic landscape and pathologic significance of POLE mutant CRC remain poorly reported. This study aimed to characterize the clinicopathological features and genomic landscape of CRC harborage POLE mutations and to investigate the consequences of coexisting genetic changes.
Methods
We identified thirty-four cases of CRC with POLE mutations from our institution’s database using our next-generation sequencing gene panels, including the 161-gene panel for the 2016–2021 cases and the 505-gene panel for the 2022–2023 case. We collected clinicopathological data (age, sex, tumor site and classification) and performed comprehensive next-generation sequencing. Survival outcomes were assessed by review of patients’ medical records at the time of data collection, with survival status determined based on the most recent clinical follow-up available with overall survival as the primary endpoint and a median follow-up time of 20.5 months. Statistical analyses, including chi-square test and CoMutation plot, were performed using Python.
Results
The 34 patients enrolled had a mean age of 60.5 years (range: 37–84). Tumors were in the colon (26 cases, 77%) and rectum (8 cases, 23%), with a mismatch repair failure rate of 29%. Next-generation sequencing of a panel of 505 genes revealed this POLE Mutations were predominantly missense (89%). The mutations were distributed in several regions: 11.4% in the exonuclease region, 25.7% in the catalytic region, 20% in an unknown functional region, and 42.9% in a non-functional region. The mean number of genomic mutations per case was 12.1 ± 12.3. CoMutation analysis identified two subsets: high genomic mutation (>5 mutations, range 6–60 mutations, n = 22) and low mutation (. Specifically, TP53 mutations occurred in 55% of cases and defects in DNA double-strand repair proteins occurred in 47% of cases. POLE mutated CRC with coexisting DNA repair mutations showed a significantly higher total number of genomic mutations (19.9 ± 14.4, mutation range 7–60, chi-square = 5.1, p-value = 0.02). Although a comparison of survival between TP53 wild-type and TP53 mutant subgroups POLE– Mutant CRC not statistically significant (p = 0.37), showed a trend towards better survival in the TP53 wild type group.
conclusions
POLE Mutant adenocarcinoma represents a distinct molecular and clinicopathological entity with two subgroups. A subgroup is characterized by traditional colon carcinoma driver mutations and secondary ones POLE mutations with results that reflect more traditional colorectal carcinoma and the other is due POLE mutations with a corresponding hypermutant phenotype and better outcomes. Further studies of these two subgroups may allow improved prognosis of patients with POLE mutated colorectal carcinoma and may support the use of immunotherapy for guided individuals POLE mutations. Furthermore, these data suggest that the classification of POLE Mutant colorectal carcinoma is incomplete and requires further investigation to fully understand its implications. POLE mutations.
