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Ultra-mutated colorectal cancer patients with POLE driver mutations exhibit distinct clinical patterns.

ABSTRACT: POLE mutations, which lead to an ultramutated phenotype in colorectal cancer (CRC), have been reported as a promising marker in immunotherapy. We performed sequencing of CRC cases in Zhejiang University (ZJU) and extracted obtainable data from recently published results, including The Cancer Genome Atlas (TCGA), Japanese studies and clinical trials, to present clinical patterns of POLE driver-mutated CRC and reveal its heterogeneity. The rate of somatic POLE driver mutations has been reported as 2.60% (ZJU cohort), 1.50% (TCGA cohort), 1.00% (Japan cohort), and 1.00% (Lancet cohort). POLE driver mutations show a clearly increased mutation burden (mean TMB: 217.98 mut/Mb in ZJU; 203.13 mut/Mb in TCGA). Based on pooled data, more than 70.00% of patients with POLE driver mutations were diagnosed before they were 55 years old and at an early disease stage (Stage 0-II >70.00%), and more than 70.00% were male. Among Asian patients, 68.40% developed POLE driver mutations in the left-side colon, whereas 64.00% of non-Asian patients developed them in the right-side colon (p < 0.01). 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.

SUBMITTER: Hu H

PROVIDER: S-EPMC7826451 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Ultra-mutated colorectal cancer patients with POLE driver mutations exhibit distinct clinical patterns.

Hu Hanguang H Cai Wen W Wu Dehao D Hu Wangxiong W Dong Wang Li L Mao Jianshan J Zheng Shu S Ge Weiting W

Cancer medicine 20201030 1

POLE mutations, which lead to an ultramutated phenotype in colorectal cancer (CRC), have been reported as a promising marker in immunotherapy. We performed sequencing of CRC cases in Zhejiang University (ZJU) and extracted obtainable data from recently published results, including The Cancer Genome Atlas (TCGA), Japanese studies and clinical trials, to present clinical patterns of POLE driver-mutated CRC and reveal its heterogeneity. The rate of somatic POLE driver mutations has been reported as ...[more]

PMID: 33125191

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Project description:Objective: Studies have demonstrated an association between somatic POLE exonuclease domain mutations (EDMs) and the prognosis of colorectal cancer (CRC). However, the prognostic value of POLE non-EDMs remains unclear. This retrospective study aimed to explore the possible relationships between POLE mutation subtypes and CRC prognosis. Methods: The 272 CRC patients from the First Affiliated Hospital of Zhengzhou University (ZZ cohort) and 499 CRC patients from The Cancer Genome Atlas database (TCGA cohort) were retrospectively collected. The cases were divided into subgroups based on POLE mutation sites and microsatellite instability (MSI) status. The continuous variables were compared among three subgroups with Kruskal-Wallis tests. Pairwise comparisons between three groups were performed by Bonferroni correction method, and adjusted p < 0.05 was considered statistically significant. The categorical variables were compared with Chi-square test and Fisher’s exact test. The Kaplan—Meier curves and Cox regression models were conducted to evaluate prognostic values of POLE mutations. Results: In the ZZ cohort, POLE EDMs (2.6%) were significantly associated with younger age (p = 0.018) and localized in the left colon (p = 0.001). POLE non-EDMs were significantly associated with MSI-high status (p < 0.001) and localization in the right colon (p = 0.001). In the TCGA cohort, the tumor mutation burden (TMB) of both POLE EDM tumors (p < 0.001) and POLE non-EDM tumors (p < 0.001) was significantly higher than that of POLE wild-type (WT) tumors. A similar trend was observed in the ZZ cohort, although there were no significant differences. In the ZZ cohort, the POLE EDM group had higher progression-free survival (PFS) (p = 0.002) and overall survival (OS) (p = 0.042) than the POLE non-EDM group and POLE WT group. We also report one CRC patient harboring a germline POLE mutation who received camrelizumab and exhibited long-term stable disease. Conclusion: Both POLE-EDMs and POLE non-EDMs were associated with significantly increased TMB in CRC and may be biomarkers for CRC treatment and prognosis. Current evidence does not support an effect of POLE non-EDMs on PFS and OS. A significant association between POLE EDMs and improved PFS and OS may exist, but future studies with larger sample sizes are needed. Entire coding region of the POLE gene should be screened.

Project description:BackgroundMutations in the POLE gene result in an ultra-hypermutated phenotype in colorectal cancer (CRC); however, the molecular characterisation of epigenetic alterations remains unclear. We examined the genetic and epigenetic profiles of POLE-mutant CRC to elucidate the clinicopathological features of the associated genetic and epigenetic alterations.ResultsTumour tissues (1,013) obtained from a cohort of patients with CRC were analysed to determine associations between the proofreading domain mutations of POLE with various clinicopathological variables, microsatellite instability (MSI) status, BRAF and KRAS mutations, and the methylation status of key regions of MLH1, MGMT, and SFRP2 promoters by calculating the methylation scores (range 0-6). Only four cases (0.4%) exhibited pathogenic POLE hotspot mutations (two p.P286R [c.857C > G], one p.V411L [c.1231G > C], and p.S459F [c.1376C > T] each), which were mutually exclusive to BRAF and KRAS mutations and MSI. CRC patients were divided into four subgroups: patients with POLE mutations (POLE, 0.4%, n = 4), patients with both MSI and extensive methylation in MLH1 (MSI-M, 2.9%, n = 29), patients with MSI but no extensive methylation in MLH1 (MSI-U, 3.6%, n = 36), and patients without MSI (non-MSI, 93.2%, n = 944). The POLE group was younger at diagnosis (median 52 years, P < 0.0001), with frequent right-sided tumour localisation (frequency of tumours located in the right colon was 100%, 93.1%, 36.1%, and 29.9% in POLE, MSI-M, MSI-U, and non-MSI, respectively; P < 0.0001), and was diagnosed at an earlier stage (frequency of stages I-II was 100%, 72.4%, 77.8%, and 46.6% in POLE, MSI-M, MSI-U, and non-MSI, respectively, P < 0.0001). The mean methylation score in POLE was not different from that in MSI-U and non-MSI, but the methylation signature was distinct from that of the other subgroups. Additionally, although the examined number of POLE-mutant tumours was small, the number of CD8-positive cells increased in tumours with partial methylation in the MLH1 gene.ConclusionsCRC 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.

Project description:Background and purposeIndividualized therapy in endometrial cancer, the most common gynaecologic cancer in the developed world, focuses on identifying specific molecular subtypes. Mutations in the exonuclease domain of the DNA polymerase epsilon (POLE) gene define one such subtype, which causes an ultra-mutated tumour phenotype. These tumours may have an improved progression-free survival and may be receptive to specific therapies. However, the clinical phenotype of these tumours is unknown. The objective of this study was to evaluate the clinical and genetic features of POLE-mutated tumours from a large cohort of women whose cases are characterized by: (1) the availability of detailed clinical and lifestyle data; (2) mutation analysis; and (3) long-term follow-up.MethodsA total of 604 patients with endometrial cancer were included in the study. Data from a detailed questionnaire, including lifestyle and family history information, provided extensive pertinent information on the patients. Sequencing of exons 9-14 of the POLE gene was performed. Follow-up data were gathered and analysed.ResultsHotspot pathogenic POLE mutations were identified in N = 38/599 patients (6.3%). Patients with a POLE-mutated tumour were significantly younger, were more often nulliparous, and had a history of smoking. POLE-mutated tumours were more frequently aneuploid. Prognosis for patients with hotspot POLE-mutated tumours was significantly better in comparison with patients with non-mutated tumours; however careful selection of pathogenic mutations is essential to the definition of this prognostically favourable group.ConclusionsThis study demonstrates that POLE-mutated endometrial cancer is significantly associated with previously unknown clinicopathologic characteristics. Outcome in POLE-mutated tumours was excellent in cases with hotspot mutations. Our results suggest that prediction of excellent outcome in cases of POLE-mutated EMCA should be restricted to cases of EMCA with hotspot mutations until further data are available on the rising number of mutations with unknown significance.

Dataset Information

Ultra-mutated colorectal cancer patients with POLE driver mutations exhibit distinct clinical patterns.

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Ultra-mutated colorectal cancer patients with POLE driver mutations exhibit distinct clinical patterns.

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