POLE P286R

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.

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.

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.

This report highlights the clinical importance of next-generation sequencing technology in diagnosing rare tumours and investigating novel mechanisms for developing exceptional genetic diseases.

"Background In the TRIBE2 study, molecularly unselected and untreated mCRC patients were randomized to receive FOLFOXIRI/bevacizumab (bev) followed by the same agents after disease progression (PD) or FOLFOX/bev followed by FOLFIRI/bev after PD...Legal entity responsible for the study The author. Funding GONO Foundation."

"Background: In the TRIBE2 study molecularly unselected and untreated mCRC patients were randomized to receive FOLFOXIRI/bevacizumab (bev) followed by the same agents after disease progression (PD) or FOLFOX/bev followed by FOLFIRI/bev after PD... TML high tumors are not limited to MSI-high ones but showed POLE or MSH6 somatic mutation and shower longer PFS and OS. No differences are reported between TML low and intermediate tumors. Molecular alterations predictive of benefit from targeted strategies currently available are detectable only in a small percentage of mCRCs."