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

Letter. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer
Letter. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer
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. 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?×?10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42?×?10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10?×?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.
cancer genetics
0028-0836
406-410
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Loveday, Chey
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Renwick, Anthony
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Rivas, Manuel A.
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Hanks, Sandra
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Cook, Jackie
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Eccles, Diana
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Henderson, Alex
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Kumar, Ajith
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McCarthy, Mark I.
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Turnbull, Clare
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Reis-Filho, Jorge S.
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Antoniou, Antonis C.
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Lord, Christopher J.
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Donnelly, Peter
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Rahman, Nazneen
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Ruark, Elise, Snape, Katie, Humburg, Peter, Loveday, Chey, Bajrami, Ilirjana, Brough, Rachel, Rodrigues, Daniel Nava, Renwick, Anthony, Seal, Sheila, Ramsay, Emma, Duarte, Silvana Del Vecchio, Rivas, Manuel A., Warren-Perry, Margaret, Zachariou, Anna, Campion-Flora, Adriana, Hanks, Sandra, Murray, Anne, Pour, Naser Ansari, Douglas, Jenny, Gregory, Lorna, Rimmer, Andrew, Walker, Neil M., Yang, Tsun-Po, Adlard, Julian W., Barwell, Julian, Berg, Jonathan, Brady, Angela F., Brewer, Carole, Brice, Glen, Chapman, Cyril, Cook, Jackie, Davidson, Rosemarie, Donaldson, Alan, Douglas, Fiona, Eccles, Diana, Evans, D. Gareth, Greenhalgh, Lynn, Henderson, Alex, Izatt, Louise, Kumar, Ajith, Lalloo, Fiona, Miedzybrodzka, Zosia, Morrison, Patrick J., Paterson, Joan, Porteous, Mary, Rogers, Mark T., Shanley, Susan, Walker, Lisa, Gore, Martin, Houlston, Richard, Brown, Matthew A., Caufield, Mark J., Deloukas, Panagiotis, McCarthy, Mark I., Todd, John A., Turnbull, Clare, Reis-Filho, Jorge S., Ashworth, Alan, Antoniou, Antonis C., Lord, Christopher J., Donnelly, Peter and Rahman, Nazneen (2013) Letter. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature, 493 (7432), 406-410. (doi:10.1038/nature11725). (PMID:23242139)

Record type: Article

Abstract

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. 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?×?10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42?×?10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10?×?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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More information

e-pub ahead of print date: 16 December 2012
Published date: 17 January 2013
Keywords: cancer genetics
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 352324
URI: http://eprints.soton.ac.uk/id/eprint/352324
ISSN: 0028-0836
PURE UUID: d5c447bf-6098-481b-b35e-cf45ca3e06a7
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

Catalogue record

Date deposited: 16 May 2013 10:32
Last modified: 15 Mar 2024 02:40

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Contributors

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

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