Analysis of the molecular typing and clinicopathological features of POLE and POLD1 gene mutations in middle-aged and elderly patients with colorectal cancer / 中华老年医学杂志

ABSTRACT

Objective:To examine the clinicopathological and molecular pathological characteristics of patients with colorectal cancer(CRC)who have mutations in the POLE and POLD1 genes.Methods:In this study, we retrospectively collected data from 276 middle-aged and elderly patients aged 45 years and over who were diagnosed with colorectal cancer at Beijing Hospital between October 2020 and September 2022.We utilized next generation sequencing and bioinformatics analysis to screen for harmful germline and somatic mutations in the POLE and POLD1 genes.The study involved 276 patients, who were divided into three groups based on their genetic mutations.The deleterious mutation group had 6 cases, the mutation of unknown significance group had 18 cases, and the wild type group had 252 cases.We also collected clinical and pathological features of the patients and analyzed their correlation with other molecular pathological results such as tumor mutation burden(TMB), microsatellite instability(MSI), and gene co-mutation.Results:No germline mutations were detected in the POLE and POLD1 genes across all patients.Out of the 276 patients, 18(6.5%)were found to carry POLE mutations.Among these, 6(2.2%)were classified as deleterious mutations, 12(4.3%)were positive for POLE mutations of unknown significance, and the remaining patients had wild type POLE genes.Out of the 276 patients, POLD1 gene mutations of unknown significance were found in 10 patients(3.6%). Among the 276 patients, 5 cases(1.8%)carried two types of gene mutations.Patients in the deleterious mutation group showed earlier tumor stage( P<0.05)and a higher prevalence of low-grade tumor budding( P<0.05), with 6 patients being affected by this.Compared to the wild type group, colon cancer patients showed a higher frequency of deleterious mutations and variants of unknown significance in the poorly differentiated group( P<0.05). The median TMB in the deleterious mutation group was 257.76 muts/Mb, 74.4 muts/Mb in the mutation of unknown significance group, and 5.81 muts/Mb in the wild type group.The study found significant differences in TMB-H status among the three groups, with all P-values less than 0.01.MSI-H status was detected in 1 case(16.7%, 1/6), 14 cases(77.8%, 14/18), and 18 cases(7.1%, 18/276)in the deleterious mutation group, variant of undetermined significance group, and wild type group, respectively.Notably, patients with variants of undetermined significance had a higher MSI-H status than patients with wild type and POLE deleterious mutations, with all P-values less than 0.01.The frequencies of co-mutations in KRAS, NRAS, BRAF, and PIK3CA were higher in the deleterious mutation group compared to the mutation of undetermined significance group and wild type group(all P<0.05). Conclusions:Colorectal cancer(CRC)patients with harmful mutations and variants of undetermined significance exhibit unique clinicopathological features.Patients with variants of undetermined significance are more likely to develop colon cancer, show poor differentiation, and have higher frequencies of TMB-H(tumor mutational burden)and MSI-H(microsatellite instability-high).