Exonuclease Domain Of Polymerase Epsilon Research Articles

Fast and reliable Sanger POLE sequencing protocol in FFPE tissues of endometrial cancer.

The new classification of endometrial carcinoma (EC) requires molecular interpretation of somatic polymerase epsilon (POLE) exonuclease domain mutations. The identification of pathogenic mutations within the POLE gene defines the important subtype of ultramutated tumours ("POLE-ultramutated") with specified prognostic and predictive utility. POLE somatic mutations are present in 7-12% of ECs, usually high-grade tumours with aggressive appearance. Molecular analysis of the POLE gene can be performed using a qPCR test, the Sanger sequencing method, a next generation sequencing (NGS) panel test and also in situ hybridisation (IHC) assay. We describe our current approach of identification of POLE mutations using Sanger sequencing technology, which is still the most robust, accurate and fast technique to sequence DNA. We present a reliable protocol for Sanger sequencing of the entire sequence coding exonuclease domain of POLE - exons 9, 10, 11, 12, 13 and 14 (codons 268-491) with 5-10 nucleotides in exon/intron boundaries (reference sequences: NM_006231.4, NP_006222.2). The protocol has been optimized for formalin-fixed, paraffin-embedded (FFPE) EC tissues. The method developed in our laboratory allows better diagnosis of patients with EC according to current standards.

Tumor mutation burden in colorectal cancers with POLE exonuclease and non-exonuclease domain variants.

224 Background: Driver mutations in the exonuclease domain (ExoD) of DNA polymerase epsilon ( POLE) have been associated with high tumor mutation burden (TMB). High TMB is an important marker for immunotherapy, and thus understanding the mechanisms that lead to high TMB is an area of active investigation. Many tumors with POLE ExoD driver mutations have additional POLE variants of uncertain significance (VUS). Some of these VUS lie within the ExoD, while most lie outside the ExoD. This study investigates the role of such POLE VUS on TMB and POLE functionality of ExoD-mutated tumors. Methods: Retrospective colorectal cancer (CRC) genomic profiles from Caris Life Sciences (n=1,870) were separated into groups based on the presence of POLE ExoD mutations and the TMB status. Groups were defined as: ‘TMB-high (TMB-H) POLE ExoD driver without additional POLE VUS’, ‘TMB-H POLE ExoD driver plus POLE VUS’, and ‘TMB-low (TMB-L) POLE variant(s) without ExoD driver’. An additional group with ‘TMB-H POLE variant(s) without ExoD driver’ was identified as potentially novel drivers for future study. The microsatellite instability status (MSI or MSS) was also considered. The level of TMB, the presence of polymerase proofreading-associated mutational signatures and POLE stability/functionality analyzed using AlphaFold2 models and Rosetta Molecular Modeling Suite, were evaluated. Results: POLE variants were identified in 4.9% of the CRCs studied (92/1870). In all, 52.2% (48/92) of those tumors were TMB-H, and 38.0% (35/92) of them contained POLE ExoD drivers. The highest median TMB (mTMB) was found in the ‘TMB-H POLE ExoD driver plus POLE VUS’ group, and this was significantly different from the ‘TMB-H POLE ExoD driver without additional POLE VUS’ and the ‘TMB-L POLE variant without ExoD driver’ group, even when MSI tumors were excluded (p<0.001, Mann-Whitney). These results were validated in TCGA CRC tumors and in other tumor types. Within the ‘TMB-H POLE ExoD driver plus POLE VUS’ group, the mTMB increased with the number of accumulated POLE VUS (p<0.001, Mann Whitney). The nucleotide sequence context of 77.8% of the POLE VUS matched mutational spectra associated with POLE ExoD defects, suggesting that most of the POLE VUS are secondary to the ExoD driver mutation. Finally, the majority of POLE VUS within ‘TMB-H POLE ExoD driver plus POLE VUS’ group have a predicted effect on POLE stability and/or function. Conclusions: Our results suggest that the presence of secondary POLE non-driver variants increase TMB in POLE ExoD-mutated tumors. Although still preliminary, these data could impact prognosis and response to immune checkpoint inhibitors in patients. [Table: see text]

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In This Issue| June 02 2022 In This Issue Author & Article Information Online Issn: 2159-8290 Print Issn: 2159-8274 ©2022 American Association for Cancer Research.2022American Association for Cancer Research. Cancer Discov (2022) 12 (6): 1397–1399. https://doi.org/10.1158/2159-8290.CD-12-6-ITI Related Content A commentary has been published: Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor A commentary has been published: Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL6-Mediated Therapy Resistance in Pancreatic Cancer A commentary has been published: Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML View more A commentary has been published: Integrated Multiomic Profiling Identifies the Epigenetic Regulator PRC2 as a Therapeutic Target to Counteract Leukemia Immune Escape and Relapse A commentary has been published: The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution A commentary has been published: Precision Combination Therapies Based on Recurrent Oncogenic Coalterations A commentary has been published: PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon A commentary has been published: Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer A commentary has been published: Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record June 2 2022 Citation In This Issue. Cancer Discov 1 June 2022; 12 (6): 1397–1399. https://doi.org/10.1158/2159-8290.CD-12-6-ITI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Proofreading defects produced from mutations in the DNA polymerase epsilon (POLE) gene contribute to a hypermutated genome that can potentially sensitize tumors to immune checkpoint blockade. Despite this, many POLE-mutant tumors do not demonstrate a robust response to this type of therapy. Rousseau and colleagues conducted a multicenter clinical trial in patients with POLE-mutated solid tumors and showed that only mutations in the DNA binding or catalytic site of the exonuclease domain of POLE contributed to high tumor burden and subsequent increases to T-cell infiltration and response rates to anti–PD-1 therapy, suggesting their use as a biomarker of anti–PD-1 response. See article, p. 1435. Escape from the “graft-versus-tumor” effect represents the main driver of leukemia relapses after allogeneic hematopoietic cell transplantation. In up to 40% of cases, the expression of HLA class II molecules is lost from the surface of leukemic cells, without evidence of... You do not currently have access to this content.

A Multiplex SNaPshot Assay is a Rapid and Cost-Effective Method for Detecting POLE Exonuclease Domain Mutations in Endometrial Carcinoma.

Determining the replicative DNA polymerase epsilon ( POLE) mutation status in endometrial carcinomas (ECs) has important clinical implications given that the majority of "ultramutated" tumors harboring pathogenic exonuclease domain mutations in POLE ( POLE mut) have a favorable prognosis, even among high-grade histotypes. Currently, there are no specific morphologic or immunophenotypic features that allow accurate detection of POLE mut tumors without molecular testing. Consequently, identifying POLE mut tumors has been challenging without employing costly and/or time-consuming DNA sequencing approaches. Here we developed a novel SNaPshot assay to facilitate routine and efficient POLE mutation testing in EC. The SNaPshot assay interrogates 15 nucleotide sites within exons 9, 11, 13, and 14 encoding the POLE exonuclease domain. The variant sites were selected based on recurrence, evidence of functional impact, association with high tumor mutation burden and/or detection in EC clinical outcome studies. Based on the pathogenic somatic variants reported in the literature, the assay is predicted to have a clinical sensitivity of 90% to 95% for ECs. Validation studies showed 100% specificity and sensitivity for the variants covered, with expected genotypic results for both the positive (n=11) and negative (n=20) patient controls on multiple repeat tests and dilution series. Analytic sensitivity was conservatively approximated at a 10% variant allele fraction (VAF), with documented detection as low as 5% VAF. As expected, the SNaPshot assay demonstrated greater sensitivity than Sanger sequencing for VAFs below 20%, an important characteristic for somatic mutation detection. Here we have developed and validated the first SNaPshot assay to detect hotspot POLE mutations. While next-generation sequencing and Sanger sequencing-based approaches have also been used to detect POLE mutations, a SNaPshot approach provides useful balance of analytical sensitivity, cost-effectiveness, and efficiency in a high-volume case load setting.

Abstract 2413: POLE gene mutations in African Americans colorectal cancer

Abstract Background: Most focus in genetic instability in colon carcinogenic transformation was on DNA Mismatch Repair (MMR) genes alterations as they relate to the microsatellite instability phenotype. However, POLE gene mutations can also be instrumental in triggering genetic instability, at even higher magnitude of genome mutation rate. Aim: To assess POLE gene mutations in African Americans with colorectal cancer (CRC). Methods: Data from Whole exome sequencing of 12 CRC African American tumors was searched to scan POLE gene mutations. All detected mutations were checked in tumors and matched normal. The detected mutations were validated in a second set of samples that were sequenced using POLE gene targeted sequencing. Detected and validated mutations were checked in available databases such as COSMIC and dbSNP to determine novel mutations in our population that is at high risk of aggressive CRC. Results: Six out of 12 patients (50%) displayed mutations in POLE gene. There were 41 detected mutations, 11 are novel mutations and 15 are amino-acid changing. Nine of these were non-synonymous and predicted to have deleterious effects. All these mutations were validated using targeted sequencing. In comparison to DNA MMR, POLE gene has four folds more mutations than MSH2gne (10 mutations and MSH6 (11 mutations and two fold more than MSH3 gene (20 mutations) in the same set of 12 cancer/matched normals. The POLE mutations heterozygous/homozygous status was overall similar in normal and matched normal. However, most of the mutations were homozygous. Conclusion: POLE gene mutations are increasingly recognized as another important element in genetic instability. Our data shows that mutations affecting this gene are likely more significant than those affecting DNA MMR genes. Moreover, POLE mutations might be more consequential, especially those affecting its exonuclease domain of polymerase epsilon, proofreading catalytic subunit. Microsatellite-stable, hypermutated CRCs might need to be explored for POLE gene mutations to track the origin of high mutation rates. Citation Format: Hassan Brim, Babak Shokrani, Hamed Azimi, Sudhir Varma, Edward Lee, Hassan Ashktorab. POLE gene mutations in African Americans colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2413.

POLE Mutation Characteristics in a Chinese Cohort with Endometrial Carcinoma.

ObjectiveTo study the characteristics of polymerase epsilon (POLE) exonuclease domain mutations in Chinese patients with endometrial carcinoma (EC).MethodsThis study analyzed data from 529 patients with EC in The Cancer Genome Atlas (TCGA) and 467 EC patients evaluated at the Shanghai First Maternity and Infant Hospital (SFMIH). POLE mutation heterogeneity was analyzed in paired curettage and hysterectomy samples from 120 SFMIH patients. Sanger sequencing identified mutations in the POLE exonuclease domain, and correlations between POLE mutation status and various clinicopathological features were determined by chi-squared testing and Cohen’s kappa analysis, with Kaplan–Meier survival curves generated to assess correlations between POLE mutation status and overall survival (OS).ResultsThirty-five mutations were identified in 467 samples (7.5%), and novel mutations were detected in the SFMIH cohort. Compared to the TCGA cohort, the SFMIH cohort had fewer POLE mutations when matched by age (<60) and histology (endometrioid) (p < 0.001 and p = 0.010, respectively). In our study cohort, POLE mutations were significantly associated with adjuvant treatment (p = 0.029), and patients with POLE mutations who underwent chemoradiotherapy had a poor OS (p < 0.0001). Notably, shorter OS was significantly associated with POLE mutations in hysterectomy samples from patients aged >60 years or with stage I disease in the paired curettage-hysterectomy group.ConclusionThe significant difference in POLE mutation profiles between the TCGA and SFMIH cohorts, as well as the poor consistency between the curettage and hysterectomy samples, suggests that different parameters need to be applied to determine the prognosis of patients with EC in China.

Molecular Heterogeneity of Endometrioid Ovarian Carcinoma: An Analysis of 166 Cases Using the Endometrial Cancer Subrogate Molecular Classification.

Endometrioid ovarian carcinoma (EOC) has clinical and biological differences compared with other histologic types of ovarian carcinomas, but it shares morphologic and molecular features with endometrioid endometrial carcinoma. To analyze the molecular heterogeneity of EOC according to the new molecular classification of endometrial cancer and to evaluate the prognostic significance of this molecular classification, we have analyzed 166 early-stage EOC by immunohistochemistry for mismatch repair proteins and p53 expression, and by Sanger sequencing for the exonuclease domain of polymerase epsilon (POLE EDM). In addition, we have carried out next-generation sequencing analysis of tumors with POLE EDM mutations to confirm the ultramutated profile. Eight tumors carried POLE EDM mutations and were classified as ultramutated (5%), 29 showed mismatch repair deficiency and were classified as hypermutated (18%), 16 tumors had a mutated pattern of p53 expression and were classified as p53 abnormal (11%), and 114 tumors did not have any of the previous alterations and were classified as no specific type (66%). Five tumors showed >1 classification criteria. The frequencies of ultramutated and hypermutated tumors were lower in EOC compared with the frequency reported in endometrial cancer. Subrogate molecular groups differed in both morphologic features (histologic grade, squamous and morular metaplasia, and necrosis) and immunohistochemical expression of several biomarkers (ARID1A, nuclear β-catenin, estrogen receptors, Napsin A, and HINF1B). In addition, the number of CD8 tumor-infiltrating lymphocytes was higher in ultramutated and hypermutated tumors. The most commonly mutated genes in the ultramutated group were ARID1A (100%), PIK3R1, PTEN, BCOR, and TP53 (67% each), whereas no mutations were detected in KRAS. Although the prognosis did not differ among subgroups in the multivariate analysis, a trend toward a better prognosis in POLE-mutated and a worse prognosis in p53 abnormal tumors was observed. In addition, this classification could have important therapeutic implications for the use of immunotherapy in tumors classified as ultramutated and hypermutated.

Mutational processes of distinct POLE exonuclease domain mutants drive an enrichment of a specific TP53 mutation in colorectal cancer

Cancer genomes with mutations in the exonuclease domain of Polymerase Epsilon (POLE) present with an extraordinarily high somatic mutation burden. In vitro studies have shown that distinct POLE mutants exhibit different polymerase activity. Yet, genome-wide mutation patterns and driver mutation formation arising from different POLE mutants remains unclear. Here, we curated somatic mutation calls from 7,345 colorectal cancer samples from published studies and publicly available databases. These include 44 POLE mutant samples including 9 with whole genome sequencing data available. The POLE mutant samples were categorized based on the specific POLE mutation present. Mutation spectrum, associations of somatic mutations with epigenomics features and co-occurrence with specific driver mutations were examined across different POLE mutants. We found that different POLE mutants exhibit distinct mutation spectrum with significantly higher relative frequency of C>T mutations in POLE V411L mutants. Our analysis showed that this increase frequency in C>T mutations is not dependent on DNA methylation and not associated with other genomic features and thus specifically due to DNA sequence context alone. Notably, we found strong association of the TP53 R213* mutation specifically with POLE P286R mutants. This truncation mutation occurs within the TT[C>T]GA context. For C>T mutations, this sequence context is significantly more likely to be mutated in POLE P286R mutants compared with other POLE exonuclease domain mutants. This study refines our understanding of DNA polymerase fidelity and underscores genome-wide mutation spectrum and specific cancer driver mutation formation observed in POLE mutant cancers.

Interpretation of somatic POLE mutations in endometrial carcinoma.

Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours (‘POLE‐ultramutated’) within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole‐exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100 mut/Mb. A scoring system to assess these alterations (POLE‐score) was developed; based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE‐ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non‐EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI‐H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co‐existent with MSI‐H showed genomic alterations characteristic of POLE‐ultramutated ECs. In a pooled analysis of 3361 ECs, 13 ECs with DNA mismatch repair deficiency (MMRd)/MSI‐H and a pathogenic POLE EDM had a 5‐year recurrence‐free survival (RFS) of 92.3%, comparable to previously reported POLE‐ultramutated ECs. Additionally, 14 cases with non‐pathogenic POLE EDM and MMRd/MSI‐H had a 5‐year RFS of 76.2%, similar to MMRd/MSI‐H, POLE wild‐type ECs, suggesting that these should be categorised as MMRd, rather than POLE‐ultramutated ECs for prognostication. This work provides guidance on classification of ECs with POLE mutations, facilitating implementation of POLE testing in routine clinical care. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC).

5502 Background: This non-randomized phase 2 study evaluated the PD-L1 inhibitor avelumab in two cohorts of EC: i) MSI/ POLE cohort including ECs with immunohistochemical (IHC) loss of expression of at least one of the mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE and ii) MSS cohort including ECs with normal IHC expression of all MMR proteins. Methods: Eligibility criteria included measurable disease, unlimited prior therapies, and any EC histology. Co-primary endpoints were confirmed objective response (OR) and progression-free survival rate at 6 months (PFS6). Avelumab 10 mg/kg IV was given every 2 weeks until progression or unacceptable toxicity. In the 1st stage, 16 pts were enrolled in each cohort; if there were ≥2 ORs or ≥2 PFS6 responses, accrual would continue to the 2nd stage with enrollment of 19 additional pts. Overall, if there are ≥4 ORs or ≥8 PFS6 responses, avelumab would be considered worthy of further study in each cohort. Results: As of 12/2018, 33 pts were enrolled. The MSS cohort was closed at the 1st stage due to futility; of 16 pts in the MSS cohort, only 1 pt exhibited an OR and PFS6 response [ORR and PFS6 rate 6.25% (95% CI 0.16%-30.2%)]. Conversely, the MSI/POLE cohort reached the primary endpoint of 4 ORs after accrual of only 17 pts. Two pts in the MSI/POLE cohort did not initiate protocol therapy and were excluded from all analyses. Of 15 pts in the MSI/POLE cohort, 4 pts exhibited OR [1CR+3PRs, OR rate (ORR) 26.7% (95% CI 7.8%-55.1%)] and 6 pts (including the 4 pts with OR) exhibited PFS6 responses [PFS6 rate 40.0% (95% CI 16.3%-66.7%)], 4 ongoing and 3 approaching 2 yrs. Twenty-two pts (71%) reported treatment related toxicities, 6 patients (19%) G3 toxicities; there were no treatment-related G4 and G5 toxicities. In the MSI/POLE cohort, 5 of 6 PFS6 responses were observed in pts with ≥3 lines of prior therapy (p = 0.011) and in tumors who were PD-L1 negative by IHC. Further correlative work will be reported at the meeting. Conclusions: In EC pts stratified by MSI/POLE status, MSI vs MSS status appears to be correlated with avelumab response even in PD-L1 negative tumors. Responses in the MSI/POLE cohort were more frequent in more heavily pretreated patients, a finding that warrants further investigation. Clinical trial information: NCT02912572.

Polymerase epsilon mutations and concomitant β2-microglobulin mutations in cancer

Mutations in the exonuclease domain of polymerase epsilon (POLE), an enzyme of DNA synthesis, are involved in a newly described syndrome of colorectal polyposis and cancer, and have been associated with a high mutation burden with or without microsatellite instability (MSI) phenotype. The exonuclease domain of POLE executes a proofreading function that decreases the mutation rate during DNA replication by an estimated of one to two orders. The high mutation burden resulting from its loss of function could create a load of neo-antigens that would put the neoplastic cells in severe disadvantage of an immune attack if properly presented to the immune system. This paper investigates the mutagenic effect of different POLE mutations in various cancers, in published genomic studies and the effect that these POLE mutations have in selecting for mutations of the β2 microglobulin (B2M) gene involved in antigen presentation.

Abstract 1114: Polymerase epsilon (POLE) mutations and mutator phenotypes in colorectal and endometrial tumors.

Abstract Colorectal rectal and endometrial cancers are divided into microsatellite instable (MSI) and microsatellite stable (MSS) types. MSS tumors have chromosome instability with mutation rates of 1-10/Mb. MSI patients have a better prognosis than MSS patients and are treated less aggressively. These tumors exhibit microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP), an increased mutation rate (10-100/Mb, hypermutated). Here we demonstrate a novel class of tumor in these two diseases exhibiting an ultramutator phenotype with mutation rates exceeding 100/ Mb, MSS and chromosome stable. The ultra-high mutation rates appear to be caused by recurrent mutations in the exonuclease domain of DNA polymerase epsilon (POLE). Matched tumor and normal whole exomes for 512 colorectal and 248 endometrial cancers (TCGA data control center) were evaluated for mutation frequency and MSI status. Among the colorectal tumors, 70/512(14%) were hyper mutated, endometroid tumors had 65/248(26%) hypermutated tumors. Within the hypermutated tumors, we identified tumors with extremely high mutation rates (100 mutations/Mb) termed “ultramutated”. 14 (3%) colorectal and 17 (7%) endometrial were ultramutated. 100% of the colorectal and endometrial ultramutated contain an exonuclease domain mutation in POLE with three recurrently mutated positions: P286R/H/S and V411L and S459F, these mutations are found exclusively in ultramutated samples. The functional relevance of these mutations has been demonstrated by previous mutational analysis of the exonuclease domain in bacteria phage (T4) yeast,and mice. Disruption of residues in the active site leads to high error rates, a mutator phenotype and tumor formation. The defined exonuclease active site aligns closely with the recurrent mutation found in the ultramutated tumors. The ultramuted tumors have a distinct mutation spectrum, occur in context and exhibit strand biases. POLE exonuclease domain mutation tumors have high rates of C to A and T to G mutations with low rates of C to G and T to A. Changes of C to A occur predominately in context of 3’ and 5’ flanking T bases. This mutation spectrum and context of flanking bases suggests replicative strand bias. We found that mutations on the leading strand, exhibited a preference for C to A over G to T (60:40). Suggesting transcription-coupled repair (TCR) plays a role in ultramutation. Our results demonstrate that ultra mutated tumors are driven by recurrent mutations in the exonuclease domain of DNA polymerase epsilon. The distinct mutation spectrum, strand bias and mutation context all suggest TCR is involved in ultramutated tumors. We describe a previously unknown role of POLE in colorectal tumors as well as identification of a previously undescribed hot spot for cancer mutations. Citation Format: Eve Shinbrot, Nils Weinhold, Nikolaus Schultz, Lawrence A. Donehower, Jennifer Drummond, Kyle Chang, Richard Gibbs, Chris Sander, David A. Wheeler. Polymerase epsilon (POLE) mutations and mutator phenotypes in colorectal and endometrial tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1114. doi:10.1158/1538-7445.AM2013-1114