107 DNA polymerase epsilon catalytic subunit A (POLE) gene plays a crucial role in DNA repair and chromosomal replication. Mutations in the POLE gene have been linked to cancer, particularly colorectal carcinoma (CRC). However, the genomic landscape and pathological significance of POLE-mutant CRC remain underreported. This study aimed to characterise the clinicopathologic features and genomic landscape of CRC harbouring POLE mutations and to investigate the implications of co-occurring genetic alterations. The study was recently published in the Journal of Clinical and Translational Pathology. We identified thirty-four CRC cases with POLE mutations from our institution’s database using next-generation sequencing gene panels, including a 161-gene panel for cases from 2016–2021 and a 505-gene panel for cases from 2022–2023. We collected clinicopathologic data (age, sex, tumour site, and grading) and conducted comprehensive next-generation sequencing. Survival outcomes were assessed by reviewing patients’ medical records at the time of data collection, with survival status determined based on the most recent clinical follow-up available. Overall survival was the primary endpoint, and the median follow-up time was 20.5 months. Statistical analyses, including chi-squared testing and CoMutation plotting, were performed using Python. The 34 enrolled patients had a median age of 60.5 years (range: 37–84). Tumours were located in the colon (26 cases, 77%) and rectum (8 cases, 23%), with a mismatch repair deficiency rate of 29%. Next-generation sequencing analysis of the 505-gene panel revealed that POLE mutations were predominantly missense (89%). The mutations were distributed across various domains: 11.4% in the exonuclease domain, 25.7% in the catalytic domain, 20% in an unknown functional domain, and 42.9% in a non-functional domain. The average number of genomic mutations per case was 12.1 ± 12.3. CoMutation analysis identified two subsets: genomic mutation-high (>5 mutations; range 6–60 mutations; n = 22) and genomic mutation-low (≤5 mutations; n = 12). Notably, TP53 mutations occurred in 55% of cases, and defects in double-stranded DNA repair proteins occurred in 47% of cases. POLE-mutant CRC with co-occurring DNA repair mutations exhibited a significantly higher total number of genomic mutations (19.9 ± 14.4; range 7–60 mutations; chi-squared = 5.1; p-value = 0.02). Although a survival comparison between TP53 wild-type and TP53-mutant subgroups of POLE-mutant CRC was not statistically significant (p = 0.37), there was a trend towards better survival in the TP53 wild-type group. POLE-mutant adenocarcinoma represents a distinct molecular and clinicopathologic entity with two subgroups. One subgroup is characterised by traditional colorectal carcinoma driver mutations and secondary POLE mutations, with outcomes reflecting more traditional colorectal carcinoma. The other subgroup is driven by POLE mutations, with a corresponding ultramutant phenotype and better outcomes. Further studies of these two subgroups may allow improved prognostication for patients with POLE-mutant colorectal carcinoma and may support the use of immunotherapy for those with driver POLE mutations. Furthermore, these data suggest that the classification of POLE-mutant colorectal carcinoma is incomplete and requires further investigation to fully understand the impact of POLE mutations.
DNA polymerase epsilon catalytic subunit A (POLE) gene plays a crucial role in DNA repair and chromosomal replication. Mutations in the POLE gene have been linked to cancer, particularly colorectal carcinoma (CRC). However, the genomic landscape and pathological significance of POLE-mutant CRC remain underreported. This study aimed to characterise the clinicopathologic features and genomic landscape of CRC harbouring POLE mutations and to investigate the implications of co-occurring genetic alterations. The study was recently published in the Journal of Clinical and Translational Pathology. We identified thirty-four CRC cases with POLE mutations from our institution’s database using next-generation sequencing gene panels, including a 161-gene panel for cases from 2016–2021 and a 505-gene panel for cases from 2022–2023. We collected clinicopathologic data (age, sex, tumour site, and grading) and conducted comprehensive next-generation sequencing. Survival outcomes were assessed by reviewing patients’ medical records at the time of data collection, with survival status determined based on the most recent clinical follow-up available. Overall survival was the primary endpoint, and the median follow-up time was 20.5 months. Statistical analyses, including chi-squared testing and CoMutation plotting, were performed using Python. The 34 enrolled patients had a median age of 60.5 years (range: 37–84). Tumours were located in the colon (26 cases, 77%) and rectum (8 cases, 23%), with a mismatch repair deficiency rate of 29%. Next-generation sequencing analysis of the 505-gene panel revealed that POLE mutations were predominantly missense (89%). The mutations were distributed across various domains: 11.4% in the exonuclease domain, 25.7% in the catalytic domain, 20% in an unknown functional domain, and 42.9% in a non-functional domain. The average number of genomic mutations per case was 12.1 ± 12.3. CoMutation analysis identified two subsets: genomic mutation-high (>5 mutations; range 6–60 mutations; n = 22) and genomic mutation-low (≤5 mutations; n = 12). Notably, TP53 mutations occurred in 55% of cases, and defects in double-stranded DNA repair proteins occurred in 47% of cases. POLE-mutant CRC with co-occurring DNA repair mutations exhibited a significantly higher total number of genomic mutations (19.9 ± 14.4; range 7–60 mutations; chi-squared = 5.1; p-value = 0.02). Although a survival comparison between TP53 wild-type and TP53-mutant subgroups of POLE-mutant CRC was not statistically significant (p = 0.37), there was a trend towards better survival in the TP53 wild-type group. POLE-mutant adenocarcinoma represents a distinct molecular and clinicopathologic entity with two subgroups. One subgroup is characterised by traditional colorectal carcinoma driver mutations and secondary POLE mutations, with outcomes reflecting more traditional colorectal carcinoma. The other subgroup is driven by POLE mutations, with a corresponding ultramutant phenotype and better outcomes. Further studies of these two subgroups may allow improved prognostication for patients with POLE-mutant colorectal carcinoma and may support the use of immunotherapy for those with driver POLE mutations. Furthermore, these data suggest that the classification of POLE-mutant colorectal carcinoma is incomplete and requires further investigation to fully understand the impact of POLE mutations.