title: Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study.
abstract: Precision cancer medicine depends on defining distinct tumour subgroups using biomarkers that may occur at very modest frequencies. One such subgroup comprises patients with exceptionally mutated (ultramutated) cancers caused by mutations that impair DNA polymerase epsilon (POLE) proofreading.
  
  
  
  We examined the association of POLE proofreading domain mutation with clinicopathological variables and immune response in colorectal cancers from clinical trials (VICTOR, QUASAR2, and PETACC-3) and colorectal cancer cohorts (Leiden University Medical Centre 1 and 2, Oslo 1 and 2, Bern, AMC-AJCC-II, and Epicolon-1). We subsequently investigated its association with prognosis in stage II/III colorectal cancer by Cox regression of pooled individual patient data from more than 4500 cases from these studies.
  
  
  
  Pathogenic somatic POLE mutations were detected in 66 (1·0%) of 6517 colorectal cancers, and were mutually exclusive with mismatch repair deficiency (MMR-D) in the 6277 cases for whom both markers were determined (none of 66 vs 833 [13·4%] of 6211; p<0·0001). Compared with cases with wild-type POLE, cases with POLE mutations were younger at diagnosis (median 54·5 years vs 67·2 years; p<0·0001), were more frequently male (50 [75·8%] of 66 vs 3577 [55·5%] of 6445; p=0·0010), more frequently had right-sided tumour location (44 [68·8%] of 64 vs 2463 [39·8%] of 6193; p<0·0001), and were diagnosed at an earlier disease stage (p=0·006, χ2test for trend). Compared with mismatch repair proficient (MMR-P) POLE wild-type tumours, POLE-mutant colorectal cancers displayed increased CD8+ lymphocyte infiltration and expression of cytotoxic T-cell markers and effector cytokines, similar in extent to that observed in immunogenic MMR-D cancers. Both POLE mutation and MMR-D were associated with significantly reduced risk of recurrence compared with MMR-P colorectal cancers in multivariable analysis (HR 0·34 [95% CI 0·11-0·76]; p=0·0060 and 0·72 [0·60-0·87]; p=0·00035), although the difference between the groups was not significant.
  
  
  
  POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. This association underscores the importance of rare biomarkers in precision cancer medicine, but also raises important questions about how to identify and implement them in practice.
  
  
  
  Cancer Research UK, Academy of Medical Sciences, Health Foundation, EU, ERC, NIHR, Wellcome Trust, Dutch Cancer Society, Dutch Digestive Foundation.
authors.affiliation: Molecular and Population Genetics Laboratory, University of Oxford, Oxford, UK; Oxford Centre for Cancer Gene Research and NIHR Comprehensive Biomedical Research Centre, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Enric
authors.initials: E
authors.lastname: Domingo
authors.affiliation: Molecular and Population Genetics Laboratory, University of Oxford, Oxford, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Freeman-Mills
authors.affiliation: Molecular and Population Genetics Laboratory, University of Oxford, Oxford, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Rayner
authors.affiliation: Cancer Genomics and Immunology Group, University of Oxford, Oxford, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Glaire
authors.affiliation: Molecular and Population Genetics Laboratory, University of Oxford, Oxford, UK.
authors.forename: Sarah
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authors.lastname: Briggs
authors.affiliation: Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, Amsterdam, Netherlands.
authors.forename: Louis
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authors.affiliation: Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, Amsterdam, Netherlands.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Fessler
authors.affiliation: Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, Amsterdam, Netherlands.
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Department of Pathology, Leiden, Netherlands.
authors.forename: Arnoud
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authors.affiliation: Department of Pathology, Leiden, Netherlands.
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authors.lastname: Morreau
authors.affiliation: Department of Pathology, Leiden, Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.affiliation: Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Liefers
authors.affiliation: K G Jebsen Colorectal Cancer Research Centre, Oslo, Norway; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.affiliation: K G Jebsen Colorectal Cancer Research Centre, Oslo, Norway; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Stine A
authors.initials: SA
authors.lastname: Danielsen
authors.affiliation: K G Jebsen Colorectal Cancer Research Centre, Oslo, Norway; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Anita
authors.initials: A
authors.lastname: Sveen
authors.affiliation: K G Jebsen Colorectal Cancer Research Centre, Oslo, Norway; Department of Gastrointestinal Surgery, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Arild
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authors.lastname: Nesbakken
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Inti
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authors.lastname: Zlobec
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Alessandro
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authors.lastname: Lugli
authors.affiliation: Molecular and Population Genetics Laboratory, University of Oxford, Oxford, UK; Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Viktor H
authors.initials: VH
authors.lastname: Koelzer
authors.affiliation: Department of Medical Oncology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Martin D
authors.initials: MD
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authors.affiliation: Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
authors.forename: Sergi
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authors.lastname: Castellví-Bel
authors.affiliation: Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
authors.forename: Jenifer
authors.initials: J
authors.lastname: Muñoz
authors.affiliation: Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: de Bruyn
authors.affiliation: Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of Histopathology, UCL, London, UK.
authors.forename: Marco
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authors.lastname: Novelli
authors.affiliation: Department of Histopathology, UCL, London, UK.
authors.forename: Kay
authors.initials: K
authors.lastname: Lawson
authors.affiliation: Department of Histopathology, UCL, London, UK.
authors.forename: Dahmane
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authors.lastname: Oukrif
authors.affiliation: Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Eleni
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authors.lastname: Frangou
authors.affiliation: Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Dutton
authors.affiliation: Department of Molecular Digestive Oncology, University of Leuven, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Epalinges, Switzerland; Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland; SIB Swiss Institute Bioinformatics, Lausanne, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK; Oxford Cancer Centre, Churchill Hospital, Oxford Radcliffe Hospitals NHS Trust, University of Oxford, Oxford, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Kerr
authors.affiliation: Oxford Cancer Centre, Churchill Hospital, Oxford Radcliffe Hospitals NHS Trust, University of Oxford, Oxford, UK; Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.affiliation: Molecular and Population Genetics Laboratory, University of Oxford, Oxford, UK; Oxford Centre for Cancer Gene Research and NIHR Comprehensive Biomedical Research Centre, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Cancer Genomics and Immunology Group, University of Oxford, Oxford, UK; Oxford Cancer Centre, Churchill Hospital, Oxford Radcliffe Hospitals NHS Trust, University of Oxford, Oxford, UK. Electronic address: dchurch@well.ox.ac.uk.
authors.forename: David N
authors.initials: DN
authors.lastname: Church
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D004257:DNA Polymerase II / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000075223:Poly-ADP-Ribose Binding Proteins / Q000235:genetics*; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; C119525:POLE protein, human