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Endometrial Cancer Precise Molecular Typing Reference Standard

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In 2013, The Cancer Genome Atlas (TCGA) classified endometrial cancer into four subtypes based on multi-omics analyses, including whole-genome, transcriptome, and proteome analyses: POLE mutation, microsatellite instability mutation, low copy number subtype, and high copy number subtype. The 2023 International Federation of Gynecology and Obstetrics (FIGO) staging recommendations dictate that all patients with endometrial cancer (EC) undergo molecular subtype testing.

On January 29, 2024, the National Comprehensive Cancer Network (NCCN) updated its guidelines for both colon and rectal cancers to version 2024.V1. Compared to the 2023 V6 NCCN guidelines, the 2024 V1 version added molecular testing for POLE and POLD1 mutations and RET fusion genes for the first time.

POLE gene Introduction

The POLE gene, located at 12q24.33, consists of 63,762 base pairs and encompasses 51 exons. It encodes the catalytic subunit of the DNA polymerase Pol epsilon, which comprises a catalytic domain and an exonuclease domain and is crucial for proofreading during DNA replication. When pathogenic mutations occur in the exonuclease domain of the POLE gene, preventing the protein from timely performing error proofreading during DNA replication, the tumor genome accumulates numerous replication errors during cell proliferation, resulting in a mutation frequency 10-100 times higher than that of normal cells (typically <10 mutations/Mb). A POLE mutation is diagnosed only when a pathogenic mutation in the exonuclease domain (exons 9-14) is detected in a tumor. Pole gene mutations can lead to tumorigenesis.

Current studies have shown that, despite the highly malignant morphology of tumors harboring POLE gene mutations, they have a favorable prognosis and are highly responsive to immunotherapy.

POLE gene Mutation

POLE mutations include both somatic and germline mutations, with a somatic mutation rate of 6%-10% and a germline mutation rate of 0.25%-4%. Germline mutations are hereditary. POLE gene mutation types include nucleotide duplications, deletions, and insertions, with the majority of mutations representing aneuploidy. POLE gene mutation testing includes hotspot mutations or pathogenic variants within the POLE exonuclease domain. The POLE exonuclease domain encompasses exons 9-14, with over 80% of pathogenic variants occurring in exons 9 and 13. Currently, 11 pathogenic variants have been identified within the POLE gene, including P286R, V411L, S297F, S459F, A456P, F367S, L424I, M295R, P436R, M444K, and D368Y. New possible pathogenic mutation sites are being reported one after another, and a few studies have confirmed pathogenic mutations outside the exonuclease domain, but their pathogenic effects need further confirmation.

POLE gene testing

Currently, the main methods for detecting POLE gene mutations include Sanger sequencing and second-generation high-throughput sequencing (NGS). The advantages of Sanger sequencing are low cost and high accuracy. It is very economical and efficient for detecting known variant sites and can be used as the gold standard for detection. However, its biggest limitation is its low coverage and sensitivity, and it cannot detect unknown variant sites. NGS technology has the advantages of high throughput, high accuracy, and rich information. However, the high cost and long detection cycle limit the promotion and application of NGS in clinical practice. In addition, to reduce detection costs and improve detection sensitivity, the target sequence can be hybridized and captured or amplicon enriched before targeted sequencing. The 2021 edition of the "Chinese Expert Consensus on Molecular Detection of Endometrial Cancer" recommends high-throughput target fragment sequencing of exons 9 to 14 of the POLE gene, especially pathogenic mutations in the exonuclease domain of the POLE gene, when conditions permit.

Endometrial cancer precise molecular typing Reference standard

CB-Gene Bio has launched a precise molecular typing standard for endometrial cancer to assist in POLE gene testing. Please feel free to contact us. Some data are shown below:

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