Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

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Abstract

Many individuals with multiple or large colorectal adenomas, or early-onset colorectal cancer (CRC), have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple adenoma and/or CRC cases, but in no controls. The susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proof-reading (exonuclease) domain of DNA polymerases ε and δ, and are predicted to impair correction of mispaired bases inserted during DNA replication. In agreement with this prediction, mutation carriers’ tumours were microsatellite-stable, but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently-described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE exonuclease domain mutations.

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Stampy: a statistical algorithm for sensitive and fast mapping of Illumina sequence reads.

Gerton Lunter, Martin Goodson (2011)

High-volume sequencing of DNA and RNA is now within reach of any research laboratory and is quickly becoming established as a key research tool. In many workflows, each of the short sequences ("reads") resulting from a sequencing run are first "mapped" (aligned) to a reference sequence to infer the read from which the genomic location derived, a challenging task because of the high data volumes and often large genomes. Existing read mapping software excel in either speed (e.g., BWA, Bowtie, ELAND) or sensitivity (e.g., Novoalign), but not in both. In addition, performance often deteriorates in the presence of sequence variation, particularly so for short insertions and deletions (indels). Here, we present a read mapper, Stampy, which uses a hybrid mapping algorithm and a detailed statistical model to achieve both speed and sensitivity, particularly when reads include sequence variation. This results in a higher useable sequence yield and improved accuracy compared to that of existing software.

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A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.

Kenneth R. Muir, Lynn Martin, Gabrielle Sellick … (2007)

Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.

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Yeast DNA polymerase epsilon participates in leading-strand DNA replication.

Zachary Pursell, Isabelle Isoz, Else-Britt Lundström … (2007)

Multiple DNA polymerases participate in replicating the leading and lagging strands of the eukaryotic nuclear genome. Although 50 years have passed since the first DNA polymerase was discovered, the identity of the major polymerase used for leading-strand replication is uncertain. We constructed a derivative of yeast DNA polymerase epsilon that retains high replication activity but has strongly reduced replication fidelity, particularly for thymine-deoxythymidine 5'-monophosphate (T-dTMP) but not adenine-deoxyadenosine 5'-monophosphate (A-dAMP) mismatches. Yeast strains with this DNA polymerase epsilon allele have elevated rates of T to A substitution mutations. The position and rate of these substitutions depend on the orientation of the mutational reporter and its location relative to origins of DNA replication and reveal a pattern indicating that DNA polymerase epsilon participates in leading-strand DNA replication.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 10 May 2013

Publication date (Electronic): 23 December 2012

Publication date (Print): February 2013

Publication date PMC-release: 27 September 2013

Volume: 45

Issue: 2

Pages: 136-144

Affiliations

[1 ]Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK

[2 ]Bioinformatics and Statistical Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK

[3 ]Section of Cancer Genetics, Brookes-Lawley Building, Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK

[4 ]Dept. of Zoology, University of Oxford, The Tinbergen Building, South Parks Road, Oxford OX1 3PS, UK

[5 ]Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK

[6 ]Research Group Human Genetics, Department of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland

[7 ]Illumina Cambridge Ltd., Chesterford Research Park, Little Chesterford, Essex CB10 1XL, UK

[9 ]Wessex Regional Genetics, Princess Anne Hospital, Southampton SO16 5YA UK

[10 ]Department of Statistics, University of Oxford, South Parks Road, Oxford OX1 3TG, UK

[11 ]Guy’s, King’s, St Thomas’ Cancer Centre, Guy’s Hospital, London SE1 9RT, UK

[12 ]Institute of Cancer, Bart’s and the London Medical School, Queen Mary College, University of London, Charterhouse Square , London EC1M 6BQ, UK

[13 ]Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 7DU, UK

[14 ]Polyposis Registry, Imperial College School of Medicine, St Mark’s Hospital Watford Road, Harrow, HA1 3UJ, UK

[15 ]Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK

[16 ]Science Division, Diamond Light Source Ltd., Diamond House, Harwell Science and Innovation Campus, Didcot, Oxfordshire, OX11 0DE, United Kingdom

[17 ]Family Cancer Clinic, Imperial College School of Medicine, St Mark’s Hospital Watford Road, Harrow, HA1 3UJ, UK

Author notes

[8]

Contributors listed at the end of the manuscript

[*]

contributed equally to this work

CORGI Consortium:

Huw Thomas ¹⁷, Eamonn Maher ¹⁸, Gareth Evans ¹⁹, Anneke Lucassen ⁹, Carole Cummings ¹⁷, Margaret Stevens ¹⁷, Lisa Walker ²⁰, Dorothy Halliday ²⁰, , Ruth Armstrong ²¹, Joan Paterson ²¹, Shirley Hodgson ²², Tessa Homfray ²², Lucy Side ²³, Louise Izatt ²⁴, Alan Donaldson ²⁵, Susan Tomkins ²⁵, Patrick Morrison ²⁶, Selina Goodman ²⁷, Carole Brewer ²⁷, Alex Henderson ²⁸, Rosemarie Davidson ²⁹, Victoria Murday ²⁹, Jaqueline Cook ³⁰, Neva Haites ³¹, Timothy Bishop ³², Eamonn Sheridan ³², Andrew Green ³³, Christopher Marks ³⁴, Sue Carpenter ³⁴, Mary Broughton ³⁴, Lynn Greenhalge ³⁵, Mohnish Suri ³⁶

¹⁸Department of Clinical Genetics, University of Birmingham, Birmingham, UK.

¹⁹Department of Clinical Genetics, University of Manchester, Manchester, UK. ²⁰Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK. ²¹Anglia Regional Genetics Service, Addenbrooke’s Hospital, Cambridge, UK. ²²South-West Thames Regional Genetics Service, St George’s Hospital, London, UK. ²³North-East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK. ²⁴South-East Thames Regional Genetics Service, Guy’s Hospital, London, UK. ²⁵South-West Regional Genetics Service, Bristol, UK. ²⁶Northern Ireland Regional Genetics Service, City Hospital, Belfast, UK. ²⁷Peninsula Clinical Genetics Service, Royal Devon and Exeter Hospital, Exeter, UK. ²⁸Northern Regional Genetics Service, International Centre for Life, Newcastle, UK. ²⁹West of Scotland Regional Genetics Service, Yorkhill Hospital, Glasgow, UK. ³⁰Sheffield Regional Genetics Service, Children’s Hospital, Sheffield, UK. ³¹North of Scotland Regional Genetics Service, Foresterhill Hospital, Aberdeen, UK. ³²Yorkshire Regional Genetics Service, St James’s Hospital, Leeds, UK. ³³Republic of Ireland Genetics Service, Our Lady’s Hospital for Sick Children, Dublin, Ireland. ³⁴The Royal Surrey County Hospital, Guildford, UK. ³⁵Department of Clinical Genetics, Royal Liverpool Children’s Hospital, Alderhay, Liverpool, UK. ³⁶Department of Clinical Genetics, City Hospital, Nottingham, UK.

WGS500 Consortium:

Steering Committee:

Peter Donnelly (Chair) ^2,10, John Bell ³⁷ , David Bentley ⁷, Gilean McVean ², Peter Ratcliffe ³⁸, Jenny Taylor ⁵, Andrew Wilkie ^5,39

Operations Committee:

Peter Donnelly (Chair) ^2,10, John Broxholme ², David Buck ², Jean-Baptiste Cazier ², Richard Cornall ³⁸, Lorna Gregory ², Julian Knight ⁴⁰, Gerton Lunter ², Gilean McVean ², Jenny Taylor ⁵, Ian Tomlinson ^1,5, Andrew Wilkie ^5,39

Sequencing & Experimental Follow up:

David Buck (Lead) ², Lorna Gregory ², Sean Humphray ^7, Zoya Kingsbury ⁷

Data Analysis:

Gilean McVean ² (Lead), Peter Donnelly ^2,10, Jean-Baptiste Cazier ², John Broxholme ², Russell Grocock ⁷, Edouard Hatton ², Chris Holmes ^2,10, Linda Hughes ², Peter Humburg ², Alexander Kanapin ², Gerton Lunter ², Lisa Murray ⁷, Andy Rimmer ²

³⁷ Office of the Regius Professor of Medicine, Richard Doll Building, Roosevelt Drive, Oxford OX3 7LF, UK; ³⁸ Henry Wellcome Building for Molecular Physiology. Centre for Cellular and Molecular Physiology. Nuffield Department of Clinical Medicine, Roosevelt Drive, Oxford OX3 7BN, UK; ³⁹ Weatherall Inst of Molecular Medicine, University of Oxford; John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK; ⁴⁰ Functional genomics of inflammation and immunity, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK

[+ ]to whom correspondence should be sent iant@ 123456well.ox.ac.uk

Author contributions CP, KH, ED, AJ, PB, AS, DC, ZK, SS, CP, ES, LCC, YM, KK, SD, EGA, IS and SH performed laboratory experiments and/or analysed those data. JBC analysed WGS data, with assistance from MK, and supervised other bioinformatic data analysis. JT, SK and IT supervised laboratory experiments. GMcV, PD and DB oversaw WGS500 analysis and CH provided additional statistical advice. LM, EB, MG, AL, CP, RR, ES, DK, SC, HT, RH and IT obtained samples. JG undertook structural analysis. RH and IT provided sequencing data and oversaw the study. IT wrote the manuscript.

Article

Manuscript ID: EMS53122

DOI: 10.1038/ng.2503

PMC ID: 3785128

PubMed ID: 23263490

SO-VID: d065b1e8-7f93-4110-a274-8e826158baea

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Funding

Funded by: Wellcome Trust :

Award ID: 084818 || WT

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Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

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Most cited references 34

Stampy: a statistical algorithm for sensitive and fast mapping of Illumina sequence reads.

A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.

Yeast DNA polymerase epsilon participates in leading-strand DNA replication.

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Cited by 357

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