POLE V411L

Integrating molecular L1CAM classification can enhance risk stratification in early-stage EC, providing valuable prognostic information to guide treatment decisions and improve patient outcomes. POLE ddPCR might be a cost-effective and easy-to-perform test as an alternative to POLE NGS.

Together with other often requested predictive biomarkers, fastGEN kits can be easily implemented in laboratories with Illumina sequencers. A user-friendly and robust bioinformatics pipeline is based on Genovesa fastGEN platform.

pPOLE were seen in both TB and LB across cancer types. The high rate of passenger mutations underscores the utility of this POLE-specific variant classification model. Because TMB can be underestimated when tumor purity is near the limit of detection for the assay, accurate detection and classification of pPOLE is critical for identifying patients who may benefit from immunotherapy.

Since P286R is a hotspot mutation in endometrioid carcinomas, patients with this variant may not respond to cladribine. Population-based pharmacogenomics studies will be required to validate our results.

Patients with advanced-stage POLE-mutated EC may show robust response to NACT. While some tumors may not require chemotherapy, further study is necessary to stratify POLE-mutated ECs and explore the role of chemotherapy in high-risk patients.

Patients with advanced-stage POLE-mutated EC may show robust response to NACT. While some tumors may not require chemotherapy, further study is necessary to stratify POLE-mutated ECs and explore the role of chemotherapy in high-risk patients.

Hotspot POLE mutations can be detected using the ddPCR assay. We suggest simultaneously evaluating POLE mutation status using ddPCR and p53/mismatch repair protein expressions using immunohistochemistry, which can rapidly and accurately determine the molecular subtype of EC.

POLE-mutated ECs are typically high grade EECs in which IH, increased TILs and BN are frequently observed. Abnormal p53 expres- sion and/or loss of MMR protein expression in high grade tumours, does not exclude POLE mutations. Patients with pathogenic POLE mutations have a favourable prognosis, despite presenting advanced stage at diagnosis.

From the largest cohort of RNA-seq from endometrioid OC to date (n = 53), we identified six hypermutated samples likely driven by POLE (frequency, 11%). Our result suggests the clinical need to screen for POLE driver mutations in endometrioid OC, which can guide enrollment in immunotherapy clinical trials.

CRC patients with POLE proofreading mutations are rare. Such mutations are observed in younger individuals, and tumours are primarily located in the right colon. Diagnosis occurs at an earlier stage, and distinct epigenetic alterations may be associated with CD8 cell infiltration.

Our results realved a remarkable positive correlation between POLE mutation and TMB level in a Chinese colorectal cancer population, which suggests POLE gene will be a promising biomarker of immunotherpy for MSS colorectal tumor.

The distribution of TIL in EC differs according to the molecular subtypes. Our data suggest the possibility of predicting subtypes through TIL analysis, and provide insight into treatment through TME modulation.

Targeted sequencing can predict the presence of POLE mutations based on the tumor mutational burden. However, targeted sequencing alone is inadequate to classify endometrial cancers into molecular subgroups identified by The Cancer Genome Atlas.

The top three amino acid changes due to POLE driver mutations are P286R, V411L, and S459F. Investigators and physicians should ascertain the heterogeneity and clinical patterns of POLE driver mutations to be better equipped to design clinical trials and analyze the data.

A total of 4.8% CRC (four MMR-intact primary and one MMR-intact metastasis) harboured POLE mutations in amino acid 286 in exon 9 (p.P286R) or exon 13 (p.V411L). POLE-mutated CRCs arose in the transverse colon and rectum, were male-predominant, younger and showed increased tumour-infiltrating lymphocytes and immune cells at the tumour-stromal interface. The patient with metastatic POLE-mutated CRC was placed on PD-1 inhibitor treatment with marked and sustained response. These data indicate that POLE-mutated CRCs have hypermutated phenotypes despite MMR-intact status, with mutation burdens higher than that in microsatellite-unstable CRCs. Given the recent approval for treatment of microsatellite-unstable cancer with immune check-point inhibitors, assessment of POLE status may help to guide therapeutic decisions for hypermutated tumours with intact MMR that would otherwise be missed by routine testing.

Although POLE mutation was associated with favorable overall survival, the combined consideration of POLE mutation status and established clinicopathologic factors in the risk assessment of endometrial cancer is more accurate than the consideration of clinicopathologic factors alone and might lead to precise and individualized therapeutic strategies.

Thus, we concluded that CRCs with POLE proofreading deficiency had characteristics distinct from those of other CRCs. Analysis of POLE proofreading deficiency may be clinically significant for personalized management of CRCs.

Funding: BMS. Clinical trial identification: NCT03012581.