title: A panoply of errors: polymerase proofreading domain mutations in cancer.
abstract: Although it has long been recognized that the exonucleolytic proofreading activity intrinsic to the replicative DNA polymerases Pol δ and Pol ε is essential for faithful replication of DNA, evidence that defective DNA polymerase proofreading contributes to human malignancy has been limited. However, recent studies have shown that germline mutations in the proofreading domains of Pol δ and Pol ε predispose to cancer, and that somatic Pol ε proofreading domain mutations occur in multiple sporadic tumours, where they underlie a phenotype of 'ultramutation' and favourable prognosis. In this Review, we summarize the current understanding of the mechanisms and consequences of polymerase proofreading domain mutations in human malignancies, and highlight the potential utility of these variants as novel cancer biomarkers and therapeutic targets.
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Rayner
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Inge C
authors.initials: IC
authors.lastname: van Gool
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Palles
authors.affiliation: Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Kearsey
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Church
mesh_terms: D004257:DNA Polymerase II / Q000235:genetics / Q000378:metabolism; D004258:DNA Polymerase III / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D012441:Saccharomyces cerevisiae / Q000235:genetics
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; C434055:POLD1 protein, human; D004257:DNA Polymerase II; D004258:DNA Polymerase III; D004259:DNA-Directed DNA Polymerase; C119525:POLE protein, human
references.citation: J Clin Oncol. 2011 Aug 10;29(23):3153-62
references.pmid: 21747089
references.citation: Genetics. 2014 Mar;196(3):677-91
references.pmid: 24388879
references.citation: Mol Cell. 2000 Sep;6(3):593-603
references.pmid: 11030339
references.citation: Bioessays. 2015 Oct;37(10):1067-73
references.pmid: 26293347
references.citation: Nat Rev Cancer. 2011 Jun;11(6):450-7
references.pmid: 21593786
references.citation: Elife. 2015 Apr 14;4:e04988
references.pmid: 25871847
references.citation: J Biol Chem. 2004 Apr 23;279(17):16895-8
references.pmid: 14988392
references.citation: Cell. 2012 Sep 14;150(6):1107-20
references.pmid: 22980975
references.citation: Genet Med. 2016 Apr;18(4):325-32
references.pmid: 26133394
references.citation: Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15138-43
references.pmid: 25277973
references.citation: Nat Rev Genet. 2008 Aug;9(8):594-604
references.pmid: 18626473
references.citation: Mol Cell. 2008 Apr 25;30(2):137-44
references.pmid: 18439893
references.citation: Cold Spring Harb Perspect Biol. 2013 Jun 01;5(6):null
references.pmid: 23732474
references.citation: Cell Cycle. 2008 Oct;7(19):3026-36
references.pmid: 18818516
references.citation: Nature. 2014 Nov 27;515(7528):568-71
references.pmid: 25428505
references.citation: Mutat Res. 2014 Mar;761:49-52
references.pmid: 24472300
references.citation: Science. 2015 Apr 3;348(6230):124-8
references.pmid: 25765070
references.citation: N Engl J Med. 2012 Jun 28;366(26):2443-54
references.pmid: 22658127
references.citation: Nucleic Acids Res. 1993 Aug 11;21(16):3821-8
references.pmid: 8367300
references.citation: Int J Oncol. 2014 Jul;45(1):77-81
references.pmid: 24788313
references.citation: Fam Cancer. 2015 Sep;14(3):437-48
references.pmid: 25860647
references.citation: Prog Nucleic Acid Res Mol Biol. 2008;82:101-45
references.pmid: 18929140
references.citation: Genome. 2006 Apr;49(4):403-10
references.pmid: 16699561
references.citation: Cell. 1989 Oct 6;59(1):219-28
references.pmid: 2790959
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15560-5
references.pmid: 12429860
references.citation: Nat Methods. 2014 Apr;11(4):361-2
references.pmid: 24681721
references.citation: Oncogene. 1999 Sep 20;18(38):5325-33
references.pmid: 10498885
references.citation: Nature. 2007 Aug 16;448(7155):820-3
references.pmid: 17671506
references.citation: J Biol Chem. 2002 Feb 8;277(6):3894-901
references.pmid: 11711545
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17101-4
references.pmid: 19805137
references.citation: Cancer Res. 2008 May 15;68(10):3551-7; discussion 3557
references.pmid: 18483233
references.citation: Nat Struct Mol Biol. 2014 Aug;21(8):664-70
references.pmid: 24997598
references.citation: Nature. 2012 Jul 18;487(7407):330-7
references.pmid: 22810696
references.citation: Gynecol Oncol. 2013 Nov;131(2):309-14
references.pmid: 23938375
references.citation: Gynecol Oncol. 2014 Jul;134(1):15-9
references.pmid: 24844595
references.citation: Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15390-5
references.pmid: 25313033
references.citation: Nat Med. 2001 Jun;7(6):638-9
references.pmid: 11385474
references.citation: Curr Biol. 2013 Apr 8;23(7):543-52
references.pmid: 23499531
references.citation: Mol Cell Biol. 1999 Mar;19(3):2000-7
references.pmid: 10022887
references.citation: Science. 1993 May 7;260(5109):812-6
references.pmid: 8484121
references.citation: Nat Genet. 2015 Mar;47(3):257-62
references.pmid: 25642631
references.citation: Nat Genet. 2013 Feb;45(2):136-44
references.pmid: 23263490
references.citation: Cancer Discov. 2015 Jan;5(1):43-51
references.pmid: 25358689
references.citation: Hum Mol Genet. 2014 Jul 1;23(13):3506-12
references.pmid: 24501277
references.citation: Mol Cell. 2015 Jul 16;59(2):163-75
references.pmid: 26145172
references.citation: Nucleic Acids Res. 2011 Mar;39(5):1763-73
references.pmid: 21036870
references.citation: Cell. 1993 Dec 3;75(5):1027-38
references.pmid: 8252616
references.citation: Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):9047-51
references.pmid: 8090767
references.citation: Cancer Cell. 2014 Jan 13;25(1):91-101
references.pmid: 24434212
references.citation: Cancer Res. 2014 Apr 1;74(7):1895-901
references.pmid: 24525744
references.citation: Cell. 1990 Sep 21;62(6):1143-51
references.pmid: 2169349
references.citation: Nature. 2014 Sep 11;513(7517):202-9
references.pmid: 25079317
references.citation: Nat Methods. 2010 Apr;7(4):248-9
references.pmid: 20354512
references.citation: Mol Cell Biol. 1993 Jan;13(1):496-505
references.pmid: 8417347
references.citation: Biochemistry. 1996 Dec 24;35(51):16621-9
references.pmid: 8987997
references.citation: Eur J Hum Genet. 2011 Mar;19(3):320-5
references.pmid: 21157497
references.citation: N Engl J Med. 2013 Jul 11;369(2):134-44
references.pmid: 23724846
references.citation: DNA Repair (Amst). 2015 May;29:23-35
references.pmid: 25758782
references.citation: J Clin Oncol. 2011 Apr 1;29(10 ):1261-70
references.pmid: 21383284
references.citation: Mod Pathol. 2015 Apr;28(4):505-14
references.pmid: 25394778
references.citation: Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):18472-7
references.pmid: 24187148
references.citation: PLoS Genet. 2011 Dec;7(12):e1002407
references.pmid: 22144917
references.citation: Hum Mol Genet. 2013 Jul 15;22(14):2820-8
references.pmid: 23528559
references.citation: Int J Cancer. 2015 Jul 15;137(2):320-31
references.pmid: 25529843
references.citation: Br J Cancer. 2015 Jul 14;113(2):299-310
references.pmid: 26172027
references.citation: PLoS Genet. 2011 Oct;7(10):e1002282
references.pmid: 22022273
references.citation: Neuro Oncol. 2015 Oct;17 (10 ):1356-64
references.pmid: 25740784
references.citation: Mutat Res. 2010 Mar 1;685(1-2):45-53
references.pmid: 19682465
references.citation: J Clin Oncol. 2015 Feb 10;33(5):426-32
references.pmid: 25559809
references.citation: Genetics. 2013 Mar;193(3):751-70
references.pmid: 23307893
references.citation: Crit Rev Oncol Hematol. 2013 Oct;88(1):154-67
references.pmid: 23562498
references.citation: JAMA Oncol. 2015 Dec;1(9):1319-23
references.pmid: 26181000
references.citation: Proc Natl Acad Sci U S A. 2015 May 12;112(19):E2467-76
references.pmid: 25827231
references.citation: Int J Gynecol Cancer. 2015 Sep;25(7):1187-93
references.pmid: 26166557
references.citation: Cancer. 2015 Feb 1;121(3):386-94
references.pmid: 25224212
references.citation: IUBMB Life. 2014 May;66(5):339-51
references.pmid: 24861832
references.citation: Oncogene. 1998 Aug 20;17(7):835-43
references.pmid: 9780000
references.citation: Mod Pathol. 2015 Jun;28(6):836-44
references.pmid: 25720322
references.citation: Nature. 2012 Aug 30;488(7413):660-4
references.pmid: 22895193
references.citation: EMBO J. 1993 Apr;12(4):1467-73
references.pmid: 8385605
references.citation: Nat Struct Mol Biol. 2014 Jan;21(1):49-55
references.pmid: 24292646
references.citation: Nature. 2014 Jul 31;511(7511):543-50
references.pmid: 25079552
references.citation: Cancer Res. 1991 Jun 15;51(12):3075-9
references.pmid: 2039987
references.citation: Clin Cancer Res. 2015 Jul 15;21(14):3347-55
references.pmid: 25878334
references.citation: Gut. 2013 Jun;62(6):812-23
references.pmid: 23408351
references.citation: Nat Rev Mol Cell Biol. 2002 May;3(5):364-76
references.pmid: 11988770
references.citation: Cancer Metastasis Rev. 2013 Dec;32(3-4):353-61
references.pmid: 23592419
references.citation: Nat Struct Mol Biol. 2009 Sep;16(9):979-86
references.pmid: 19718023
references.citation: Cell. 2005 Sep 9;122(5):693-705
references.pmid: 16143102
references.citation: Nature. 2015 Apr 16;520(7547):373-7
references.pmid: 25754329
references.citation: Cancer Discov. 2012 May;2(5):401-4
references.pmid: 22588877
references.citation: N Engl J Med. 2015 Aug 20;373(8):726-36
references.pmid: 26287849
references.citation: Nature. 2013 May 2;497(7447):67-73
references.pmid: 23636398
references.citation: Genome Res. 2014 Nov;24(11):1740-50
references.pmid: 25228659
references.citation: Cell. 1997 Nov 14;91(4):467-77
references.pmid: 9390556
references.citation: Nat Protoc. 2009;4(7):1073-81
references.pmid: 19561590
references.citation: Eur J Hum Genet. 2015 Aug;23(8):1080-4
references.pmid: 25370038
references.citation: Cancer Med. 2014 Dec;3(6):1527-38
references.pmid: 25124163
references.citation: Science. 2014 Jan 3;343(6166):88-91
references.pmid: 24310611
references.citation: Proc Natl Acad Sci U S A. 2015 May 12;112(19):E2457-66
references.pmid: 25827226
references.citation: Nat Genet. 2003 Jul;34(3):326-9
references.pmid: 12796780
references.citation: J Biol Chem. 1988 Jan 5;263(1):501-10
references.pmid: 3335506
references.citation: J Theor Biol. 2004 May 7;228(1):47-54
references.pmid: 15064082
references.citation: Curr Opin Genet Dev. 2014 Feb;24:107-13
references.pmid: 24583393
references.citation: EMBO J. 1991 Aug;10(8):2165-70
references.pmid: 1648480
references.citation: Environ Mol Mutagen. 2012 Dec;53(9):666-82
references.pmid: 23065663
references.citation: N Engl J Med. 2014 Dec 4;371(23 ):2189-99
references.pmid: 25409260
references.citation: N Engl J Med. 2015 Jun 25;372(26):2509-20
references.pmid: 26028255
references.citation: DNA Repair (Amst). 2011 Jul 15;10(7):730-3
references.pmid: 21601536
references.citation: J Natl Cancer Inst. 2014 Dec 12;107(1):402
references.pmid: 25505230
references.citation: Fam Cancer. 2015 Dec;14(4):621-8
references.pmid: 26251183
references.citation: Proc Natl Acad Sci U S A. 1987 May;84(9):2838-42
references.pmid: 3554248
references.citation: Biochemistry. 1996 Jun 25;35(25):8110-9
references.pmid: 8679562
references.citation: Nat Commun. 2014 Sep 22;5:4990
references.pmid: 25241845
references.citation: Nat Commun. 2014 Sep 19;5:5006
references.pmid: 25233892
references.citation: PLoS One. 2012;7(6):e39156
references.pmid: 22723953
references.citation: Science. 2007 Jul 6;317(5834):127-30
references.pmid: 17615360
references.citation: PLoS Genet. 2010 Nov 18;6(11):e1001209
references.pmid: 21124948
references.citation: N Engl J Med. 2012 Jun 28;366(26):2455-65
references.pmid: 22658128