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 replication1. 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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
We thank all the subjects and families that participated in the research and D. Dudakia, J. Bull and R. Linger for their assistance in recruitment. We are indebted to M. Stratton for discussions of the data and to A. Strydom for editorial assistance. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics, Oxford (funded by Wellcome Trust grant reference 090532/Z/09/Z and Medical Research Council (MRC) Hub grant G0900747 91070) for the generation of the phase 1 sequencing data. This work was funded by the Institute of Cancer Research, The Wellcome Trust, Cancer Research UK and Breakthrough Breast Cancer. We acknowledge support by the RMH-ICR National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Cancer. We acknowledge the use of DNA from the British 1958 Birth Cohort collection funded by the MRC grant G0000934 and the Wellcome Trust grant 068545/Z/02. A.C.A. is a Cancer Research UK Senior Cancer Research Fellow (C12292/A11174). P.Do. is supported by a Wolfson-Royal Society Merit Award. K.S. is supported by the Michael and Betty Kadoorie Cancer Genetics Research Programme.
This file contains Supplementary Tables 1-8.