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Mutations in POLE and survival of colorectal cancer patients--link to disease stage and treatment.

ABSTRACT: Recent molecular profiling studies reported a new class of ultramutated colorectal cancers (CRCs), which are caused by exonuclease domain mutations (EDMs) in DNA polymerase ? (POLE). Data on the clinical implications of these findings as to whether these mutations define a unique CRC entity with distinct clinical outcome are lacking. We performed Sanger sequencing of the POLE exonuclease domain in 431 well-characterized patients with microsatellite stable (MSS) CRCs of a population-based patient cohort. Mutation data were analyzed for associations with major epidemiological, clinical, genetic, and pathological parameters including overall survival (OS) and disease-specific survival (DSS). In 373 of 431 MSS CRC, all exons of the exonuclease domain were analyzable. Fifty-four mutations were identified in 46 of these samples (12.3%). Besides already reported EDMs, we detected many new mutations in exons 13 and 14 (corresponding to amino acids 410-491) as well as in exon 9 and exon 11 (corresponding to aa 268-303 and aa 341-369). However, we did not see any significant associations of EDMs with clinicopathological parameters, including sex, age, tumor location and tumor stage, CIMP, KRAS, and BRAF mutations. While with a median follow-up time of 5.0 years, survival analysis of the whole cohort revealed nonsignificantly different adjusted hazard ratios (HRs) of 1.35 (95% CI: 0.82-2.25) and 1.44 (0.81-2.58) for OS and DSS indicating slightly impaired survival of patients with EDMs, subgroup analysis for patients with stage III/IV disease receiving chemotherapy revealed a statistically significantly increased adjusted HR (1.87; 95%CI: 1.02-3.44). In conclusion, POLE EDMs do not appear to define an entirely new clinically distinct disease entity in CRC but may have prognostic or predictive implications in CRC subgroups, whose significance remains to be investigated in future studies.

SUBMITTER: Stenzinger A

PROVIDER: S-EPMC4298379 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Mutations in POLE and survival of colorectal cancer patients--link to disease stage and treatment.

Stenzinger Albrecht A Pfarr Nicole N Endris Volker V Penzel Roland R Jansen Lina L Wolf Thomas T Herpel Esther E Warth Arne A Klauschen Frederick F Kloor Matthias M Roth Wilfried W Bläker Hendrik H Chang-Claude Jenny J Brenner Hermann H Hoffmeister Michael M Weichert Wilko W

Cancer medicine 20140801 6

Recent molecular profiling studies reported a new class of ultramutated colorectal cancers (CRCs), which are caused by exonuclease domain mutations (EDMs) in DNA polymerase ϵ (POLE). Data on the clinical implications of these findings as to whether these mutations define a unique CRC entity with distinct clinical outcome are lacking. We performed Sanger sequencing of the POLE exonuclease domain in 431 well-characterized patients with microsatellite stable (MSS) CRCs of a population-based patient ...[more]

PMID: 25124163

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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: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:BACKGROUND: British 5-year survival from colorectal cancer (CRC) is below the European average, but the reasons are unclear. This study explored if longer provider delays (time from presentation to treatment) were associated with more advanced stage disease at diagnosis and poorer survival. METHODS: Data on 958 people with CRC were linked with the Scottish Cancer Registry, the Scottish Death Registry and the acute hospital discharge (SMR01) dataset. Time from first presentation in primary care to first treatment, disease stage at diagnosis and survival time from date of first presentation in primary care were determined. Logistic regression and Cox survival analyses, both with a restricted cubic spline, were used to model stage and survival, respectively, following sequential adjustment of patient and tumour factors. RESULTS: On univariate analysis, those with <4 weeks from first presentation in primary care to treatment had more advanced disease at diagnosis and the poorest prognosis. Treatment delays between 4 and 34 weeks were associated with earlier stage (with the lowest odds ratio occurring at 20 weeks) and better survival (with the lowest hazard ratio occurring at 16 weeks). Provider delays beyond 34 weeks were associated with more advanced disease at diagnosis, but not increased mortality. Following adjustment for patient, tumour factors, emergency admissions and symptoms and signs, no significant relationship between provider delay and stage at diagnosis or survival from CRC was found. CONCLUSIONS: Although allowing for a nonlinear relationship and important confounders, moderately long provider delays did not impact adversely on cancer outcomes. Delays are undesirable because they cause anxiety; this may be fuelled by government targets and health campaigns stressing the importance of very prompt cancer diagnosis. Our findings should reassure patients. They suggest that a health service's primary emphasis should be on quality and outcomes rather than on time to treatment.

Dataset Information

Mutations in POLE and survival of colorectal cancer patients--link to disease stage and treatment.

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Mutations in POLE and survival of colorectal cancer patients--link to disease stage and treatment.

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