Ershova, A. N., Martynenko, D. E., Yanus, G. A., Kuligina, E. S., Martianov, A. S., Iyevleva, A. G., Suspitsin, E. N., Aleksakhina, S. N., & Imyanitov, E. N. (2025). Detection and Molecular Features of POLE-associated Colorectal Tumors. Voprosy Onkologii, 71(2), OF–2228. https://doi.org/10.37469/0507-3758-2025-71-2-OF-2228

Abstract

Introduction. Mutations in the POLE gene are a rare cause of hypermutability in colorectal cancer (CRC). According to the results of a recent clinical study, mutations in the exonuclease domain of the POLE in metastatic CRC turned out to be a marker of a stable response to immunotherapy. The efficacy of immune checkpoint inhibitors in this category of neoplasms exceeds that in MSI-H CRC.

Aim. This work aims to summarize the experience of detecting mutations in the POLE gene in a large series of consecutive cases of metastatic CRC.

Materials and Methods. In this article, we analyzed the occurrence of hotspot mutations in the POLE gene in 7.816 colorectal cancer cases using allele-discriminatory PCR. High-resolution melting (HRM) PCR and pyrosequencing were used to analyze rare mutation variants and variants of uncertain significance.

Results. 31/7,816 (0.4 %) significant mutations were identified in POLE, the most common of which were p.V411L (n = 14), p.P286R (n = 13), p.S297F (n = 3) substitutions. POLE-associated neoplasms were significantly more frequent in patients younger than 50 years (11/766, 1.4 %, p = 0.0006) and in right-sided CRCs (9/872, 1 %, p = 0.038). They were particularly common in patients with a combination of these features (5/85, 5.9 %), in tumors with mutations in exon 4 of KRAS (6/204, 2.9 %, p = 1.571*10^-9) compared to any other damage to genes of the RAS-MAPK cascade or amplification of the HER2/neu oncogene.

Conclusion. Certain categories of CRCs require expanded investigation for the presence of rare mutations in the POLE gene.

https://doi.org/10.37469/0507-3758-2025-71-2-OF-2228

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[Janus G.A., Martianov A.S., Yershova A.N., et al. The search for frequent mutations in the POLE gene among a large cohort of "consistent" colon cancer cases: the scale of the problem. Appendix to the journal Issues of Oncology. Abstracts of the X St. Petersburg International Oncological Forum "White Nights 2024" (July 3–7, 2024, St. Petersburg). 2024; 67-68 (In Rus)].

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