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Nature. 2013 Jan 17;493(7432):406-10. doi: 10.1038/nature11725. Epub 2012 Dec 16.

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

Collaborators (396)

Aerts J, Ahmad T, Arbury H, Attwood A, Auton A, Ball SG, Balmforth AJ, Barnes C, Barrett JC, Barroso I, Barton A, Bennett AJ, Bhaskar S, Blaszczyk K, Bowes J, Brand OJ, Braund PS, Bredin F, Breen G, Brown MJ, Bruce IN, Bull J, Burren OS, Burton J, Byrnes J, Caesar S, Cardin N, Clee CM, Coffey AJ, Connell JM, Conrad DF, Cooper JD, Dominiczak AF, Downes K, Drummond HE, Dudakia D, Dunham A, Ebbs B, Eccles D, Edkins S, Edwards C, Elliot A, Emery P, Evans DM, Evans G, Eyre S, Farmer A, Ferrier IN, Flynn E, Forbes A, Forty L, Franklyn JA, Frayling TM, Freathy RM, Giannoulatou E, Gilbert P, Gordon-Smith K, Gray E, Green E, Groves CJ, Grozeva D, Gwilliam R, Hammond N, Hardy M, Harrison P, Hassanali N, Hebaishi H, Hines S, Hinks A, Hitman GA, Hocking L, Holmes C, Howard E, Howard P, Howson JM, Hughes D, Hunt S, Isaacs JD, Jain M, Jewell DP, Johnson T, Jolley JD, Jones IR, Jones LA, Kirov G, Langford CF, Lango-Allen H, Lathrop GM, Lee J, Lee KL, Lees C, Lewis K, Lindgren CM, Maisuria-Armer M, Maller J, Mansfield J, Marchini JL, Martin P, Massey DC, McArdle WL, McGuffin P, McLay KE, McVean G, Mentzer A, Mimmack ML, Morgan AE, Morris AP, Mowat C, Munroe PB, Myers S, Newman W, Nimmo ER, O'Donovan MC, Onipinla A, Ovington NR, Owen MJ, Palin K, Palotie A, Parnell K, Pearson R, Perry JR, Phillips A, Plagnol V, Prescott NJ, Prokopenko I, Quail MA, Rafelt S, Rayner NW, Reid DM, Renwick A, Ring SM, Robertson N, Robson S, Russell E, St Clair D, Sambrook JG, Sanderson JD, Sawcer SJ, Schuilenburg H, Scott CE, Seal S, Shaw-Hawkins S, Shields BM, Simmonds MJ, Smyth DJ, Somaskantharajah E, Spanova K, Steer S, Stephens J, Stevens HE, Stirrups K, Stone MA, Strachan DP, Su Z, Symmons DP, Thompson JR, Thomson W, Tobin MD, Travers ME, Turnbull C, Vukcevic D, Wain LV, Walker M, Walker NM, Wallace C, Warren-Perry M, Watkins NA, Webster J, Weedon MN, Wilson AG, Woodburn M, Wordsworth BP, Yau C, Young AH, Zeggini E, Brown MA, Burton PR, Caulfield MJ, Compston A, Farrall M, Gough SC, Hall AS, Hattersley AT, Hill AV, Mathew CG, Pembrey M, Satsangi J, Stratton MR, Worthington J, Hurles ME, Duncanson A, Ouwehand WH, Parkes M, Rahman N, Todd JA, Samani NJ, Kwiatkowski DP, McCarthy MI, Craddock N, Deloukas P, Donnelly P, Ardern-Jones A, Adlard J, Ahmed M, Attard G, Bailey K, Bancroft E, Bardsley C, Barton D, Bartlett M, Barwell J, Baxter L, Belk R, Berg J, Bernhard B, Bishop T, Boyes L, Bradshaw N, Brady AF, Brant S, Brewer C, Brice G, Bromilow G, Brooks C, Bruce A, Bulman B, Burgess L, Campbell J, Canham N, Castle B, Cetnarskyj R, Chapman C, Claber O, Coates N, Cole T, Collins A, Cook J, Coulson S, Crawford G, Cruger D, Cummings C, D'Mello L, Davidson R, Day L, Dell B, Dolling C, Donaldson A, Dorkins H, Douglas F, Downing S, Drummond S, Dubras C, Dunlop J, Durrell S, Eccles D, Eddy C, Edwards M, Edwards E, Edwardson J, Eeles R, Ellis I, Elmslie F, Evans G, Gibbons B, Gardiner C, Ghali N, Giblin C, Gibson S, Goff S, Goodman S, Goudie D, Greenhalgh L, Grier J, Gregory H, Halliday S, Hardy R, Hartigan C, Heaton T, Henderson A, Higgins C, Hodgson S, Homfray T, Horrigan D, Houghton C, Houlston RS, Hughes L, Hunt V, Irvine L, Izatt L, Jacobs C, James S, James M, Jeffers L, Jobson I, Jones W, Kennedy MJ, Kenwrick S, Kightley C, Kirk C, Kirk E, Kivuva E, Kohut K, Kosicka-Slawinska M, Kulkarni A, Kumar A, Lalloo F, Lambord N, Langman C, Leonard P, Levene S, Locker S, Logan P, Longmuir M, Lucassen A, Lyus V, Magee A, Male A, Mansour S, McBride D, McCann E, McConnell V, McEntagart M, McKeown C, McLeish L, McLeod D, Melville A, Mercer L, Mercer C, Miedzybrodzka Z, Mitra A, Morrison P, Murday V, Murray A, Myhill K, Myring J, O'Hara E, Paterson J, Pearson P, Pichert G, Platt K, Porteous M, Pottinger C, Price S, Protheroe L, Pugh S, Quarrell O, Randhawa K, Riddick C, Robertson L, Robinson A, Roffey-Johnson V, Rogers M, Rose S, Rowe S, Schofield A, Rahman N, Saya S, Scott G, Scott J, Searle A, Shanley S, Sharif S, Shaw A, Shaw J, Shea-Simonds J, Side L, Sillibourne J, Simon K, Simpson S, Slater S, Smalley S, Smith K, Snadden L, Snape K, Soloway J, Stait Y, Stayner B, Steel M, Steel C, Stewart H, Stirling D, Thomas M, Thomas S, Tomkins S, Turner H, Vandersteen A, Wakeling E, Waldrup F, Walker L, Watt C, Watts S, Webber A, Whyte C, Wiggins J, Williams E, Winchester L.

Author information

1
Division of Genetics & Epidemiology, The Institute of Cancer Research, Sutton SM2 5NG, UK.

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.

PMID:
23242139
PMCID:
PMC3759028
DOI:
10.1038/nature11725
[Indexed for MEDLINE]
Free PMC Article

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