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

Ruark, E., Snape, K., Humburg, P., Loveday, C., Bajrami, I., Brough, R., Rodrigues, D. N., Renwick, A., Seal, S., Ramsay, E., Duarte, S. D. V., Rivas, M. A., Warren-Perry, M., Zachariou, A., Campion-Flora, A., Hanks, S., Murray, A., Pour, N. A., Douglas, J., Gregory, L., Rimmer, A., Walker, N. M., Yang, T. P., Adlard, J. W., Barwell, J., Berg, J., Brady, A. F., Brewer, C., Brice, G., Chapman, C., Cook, J., Davidson, R., Donaldson, A., Douglas, F., Eccles, D., Gareth Evans, D., Greenhalgh, L., Henderson, A., Izatt, L., Kumar, A., Lalloo, F., Miedzybrodzka, Z., Morrison, P. J., Paterson, J., Porteous, M., Rogers, M. T., Shanley, S., Walker, L., Gore, M., Houlston, R., Brown, Matthew A., Caufield, M. J., Deloukas, P., McCarthy, M. I., Todd, J. A., Turnbull, C., Reis-Filho, J. S., Ashworth, A., Antoniou, A. C., Lord, C. J., Donnelly, P., & Rahman, N. (2013) Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature, 493(7432), pp. 406-410.

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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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105 citations in Scopus
97 citations in Web of Science®
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ID Code: 89277
Item Type: Journal Article
Refereed: Yes
Keywords: cancer, catalysis, enzyme activity, genetic variation, health risk, irradiation, mutation, protein, womens health, allele, article, base pairing, breast cancer, cancer risk, cancer susceptibility, controlled study, DNA repair, exon, female, gain of function mutation, gene, gene mutation, gene sequence, genetic variability, human, human cell, ionizing radiation, loss of function mutation, lymphocyte, major clinical study, ovary cancer, priority journal, protein p53 inducible protein phosphatase gene, Alleles, Breast Neoplasms, Cluster Analysis, Exons, Genetic Predisposition to Disease, Humans, Isoenzymes, Lymphocytes, Mosaicism, Ovarian Neoplasms, Phosphoprotein Phosphatases, Sequence Analysis, DNA, Tumor Suppressor Protein p53, Peru tomato mosaic virus
DOI: 10.1038/nature11725
ISSN: 0028-0836
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2013 Macmillan Publishers Limited.
Deposited On: 19 Oct 2015 22:38
Last Modified: 19 Feb 2016 04:39

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