title: Prognostic significance of POLE proofreading mutations in endometrial cancer.
abstract: BACKGROUND
  Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis.
  
  
  METHODS
  We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided.
  
  
  RESULTS
  POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06).
  
  
  CONCLUSIONS
  POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC.
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: David N
authors.initials: DN
authors.lastname: Church
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Ellen
authors.initials: E
authors.lastname: Stelloo
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Remi A
authors.initials: RA
authors.lastname: Nout
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Nadejda
authors.initials: N
authors.lastname: Valtcheva
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Jeroen
authors.initials: J
authors.lastname: Depreeuw
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Natalja
authors.initials: N
authors.lastname: ter Haar
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Aurelia
authors.initials: A
authors.lastname: Noske
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Frederic
authors.initials: F
authors.lastname: Amant
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ). iant@well.ox.ac.uk.
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Ina M
authors.initials: IM
authors.lastname: Jürgenliemk-Schulz
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Jobsen
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Carien L
authors.initials: CL
authors.lastname: Creutzberg
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D004257:DNA Polymerase II / Q000235:genetics*; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D060787:Neoplasm Grading; D016017:Odds Ratio; D000075223:Poly-ADP-Ribose Binding Proteins; D011237:Predictive Value of Tests; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; C119525:POLE protein, human