Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

Elise Ruark; Katie Snape; Peter Humburg; Chey Loveday; Ilirjana Bajrami; Rachel Brough; Daniel Nava Rodrigues; Anthony Renwick; Sheila Seal; Emma Ramsay; Silvana Del Vecchio Duarte; Manuel A. Rivas; Margaret Warren-Perry; Anna Zachariou; Adriana Campion-Flora; Sandra Hanks; Anne Murray; Naser Ansari Pour; Jenny Douglas; Lorna Gregory; Andrew Rimmer; Neil M. Walker; Tsun-Po Yang; Julian W. Adlard; Julian Barwell; Jonathan Berg; Angela F. Brady; Carole Brewer; Glen Brice; Cyril Chapman; Jackie Cook; Rosemarie Davidson; Alan Donaldson; Fiona Douglas; Diana Eccles; D. Gareth Evans; Lynn Greenhalgh; Alex Henderson; Louise Izatt; Ajith Kumar; Fiona Lalloo; Zosia Miedzybrodzka; Patrick J. Morrison; Joan Paterson; Mary Porteous; Mark T. Rogers; Susan Shanley; Lisa Walker; Martin Gore; Richard Houlston; Matthew A. Brown; Mark J. Caufield; Panagiotis Deloukas; Mark I. McCarthy; John A. Todd; Clare Turnbull; Jorge S. Reis-Filho; Alan Ashworth; Antonis C. Antoniou; Christopher J. Lord; Peter Donnelly; Nazneen Rahman; Wellcome Trust Case Control Consor

doi:10.1038/nature11725

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Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

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Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

Elise Ruark, Katie Snape, Peter Humburg, Chey Loveday, Ilirjana Bajrami, Rachel Brough, Daniel Nava Rodrigues, Anthony Renwick, Sheila Seal, Emma Ramsay, …

Nature (London), Vol.493(7432), pp.406-U152

17/01/2013

DOI: https://doi.org/10.1038/nature11725

PMCID: PMC3759028

PMID: 23242139

Abstract

Multidisciplinary Sciences

Science & Technology

Science & Technology - Other Topics

Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication(1). Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 x 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 x 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 x 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

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Title: Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer
Creators - without role: Elise Ruark - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Katie Snape - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Peter Humburg - University of Oxford
Chey Loveday - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Ilirjana Bajrami - Breakthrough
Rachel Brough - Breakthrough
Daniel Nava Rodrigues - Breakthrough
Anthony Renwick - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Sheila Seal - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Emma Ramsay - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Silvana Del Vecchio Duarte - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Manuel A. Rivas - University of Oxford
Margaret Warren-Perry - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Anna Zachariou - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Adriana Campion-Flora - Breakthrough
Sandra Hanks - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Anne Murray - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Naser Ansari Pour - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Jenny Douglas - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Lorna Gregory - University of Oxford
Andrew Rimmer - University of Oxford
Neil M. Walker - University of Cambridge
Tsun-Po Yang - Wellcome Sanger Institute
Julian W. Adlard - Chapel Allerton Hosp, Yorkshire Reg Genet Serv, Leeds LS7 4SA, W Yorkshire, England
Julian Barwell - Univ Hosp Leicester NHS Trust, Leicestershire Genet Ctr, Leicester LE1 5WW, Leics, England
Jonathan Berg - University of Dundee
Angela F. Brady - Kennedy Galton Ctr, NW Thames Reg Genet Serv, London HA1 3UJ, England
Carole Brewer - Phillips Exeter Academy
Glen Brice - George Institute for Global Health
Cyril Chapman - Birmingham Womens Hosp, W Midlands Reg Genet Serv, Birmingham B15 2TG, W Midlands, England
Jackie Cook - Sheffield Childrens NHS Fdn Trust, Sheffield Reg Genet Serv, Sheffield S10 2TH, S Yorkshire, England
Rosemarie Davidson - College Station Medical Center
Alan Donaldson - Avon
Fiona Douglas - Newcastle Upon Tyne Hosp NHS Fdn Trust, No Genet Serv, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England
Diana Eccles - University of Southampton
D. Gareth Evans - St Marys Hosp, Manchester Acad Hlth Sci Ctr, Manchester M13 9WL, Lancs, England
Lynn Greenhalgh - Liverpool Womens NHS Fdn Trust, Merseyside & Cheshire Clin Genet Serv, Liverpool L8 7SS, Merseyside, England
Alex Henderson - Newcastle Upon Tyne Hosp NHS Fdn Trust, No Genet Serv, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England
Louise Izatt - Guys & St Thomas NHS Fdn Trust, SE Thames Reg Genet Serv, London SE1 9RT, England
Ajith Kumar - Ormond
Fiona Lalloo - College Station Medical Center
Zosia Miedzybrodzka - Aberdeen Royal Infirm, Aberdeen & N Scotland Clin Genet Serv, Aberdeen AB25 2ZA, Scotland
Patrick J. Morrison - Queens University
Joan Paterson - University of Cambridge
Mary Porteous - Western Gen Hosp, SE Scotland Clin Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland
Mark T. Rogers - University of Wales
Susan Shanley - Royal Marsden NHS Fdn Trust, Dept Canc Genet, Sutton SM2 5PT, Surrey, England
Lisa Walker - University of Oxford
Martin Gore - Royal Marsden NHS Fdn, Dept Gynaecol Oncol, London SW3 6JJ, England
Richard Houlston - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Matthew A. Brown - University of Queensland
Mark J. Caufield - Queen Mary University of London
Panagiotis Deloukas
Mark I. McCarthy - University of Oxford
John A. Todd - University of Cambridge
Clare Turnbull - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Jorge S. Reis-Filho - Breakthrough
Alan Ashworth - Breakthrough
Antonis C. Antoniou - University of Cambridge
Christopher J. Lord - Breakthrough
Peter Donnelly - University of Oxford
Nazneen Rahman - Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England
Wellcome Trust Case Control Consor
Publication Details: Nature (London), Vol.493(7432), pp.406-U152
Publisher: Springer Nature
Number of pages: 7
Grant note: C12292/A11174 / Cancer Research UK Senior Cancer Research Fellow G0000934 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) CZB/4/540; ETM/137; ETM/75 / Chief Scientist Office G0800759; G0800675; G9521010; G0700491; G0000934; MR/K006584/1; G0600329 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) RMH-ICR National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Cancer; National Institute for Health Research (NIHR) Wolfson-Royal Society Merit Award; Royal Society NF-SI-0508-10275; NF-SI-0611-10219 / National Institute for Health Research; National Institute for Health Research (NIHR) Cancer Research UK G0900747 91070 / Medical Research Council (MRC) Hub grant; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 11174; 15106; 14276 / Cancer Research UK G0800759; G0000934; G0600329; G0800675; G9521010; G0700491 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Michael and Betty Kadoorie Cancer Genetics Research Programme Institute of Cancer Research 090532/Z/09/Z / Wellcome Trust
Identifiers: 9937255508331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article