Genomic landscape and clinicopathologic significance of POLE mutant colorectal carcinoma

Background and objectives

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 characterize the clinicopathologic features and genomic landscape of CRC harboring POLE mutations and to investigate the implications of co-occurring genetic alterations.

Methods

We identified thirty-four CRC cases with POLE mutations from our institution's database using the next-generation sequencing gene panels including 161-gene panel for the cases of 2016–2021 and the 505-gene panel for the case of 2022–2023. We collected clinicopathologic data (age, sex, tumor 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 with overall survival as the primary endpoint and a median follow-up time of 20.5 months. Statistical analyses, including chi-squared testing and CoMutation plotting, were performed using Python.

Results

The enrolled 34 patients had a median 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 deficiency rate of 29%. Next-generation sequencing analysis of a 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 nonfunctional 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 mutation low (. 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 is not statistical significant (p = 0.37), it showed a trend toward better survival in the TP53 wild-type group.

Conclusions

POLE mutant adenocarcinoma represents a distinct molecular and clinicopathologic entity with two subgroups. One subgroup is characterized by traditional colorectal carcinoma driver mutations and secondary POLE mutations with outcomes that reflect more traditional colorectal carcinoma, and the other is driven by POLE mutations with a corresponding ultramutant phenotype and better outcomes. Further studies of these two subgroups may allow improved prognostication of 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.