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

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 ; Ansari Pour, Naser ; 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 ; Rahman, Nazneen

Nature (London), 2013-01, Vol.493 (7432), p.406-410 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer
Autor: 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 ; Ansari Pour, Naser ; 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 ; Rahman, Nazneen
Assuntos: Alleles ; Breast cancer ; Breast Neoplasms - genetics ; Cancer ; Cluster Analysis ; Development and progression ; DNA repair ; Exons ; Female ; Gene mutations ; Genetic aspects ; Genetic Predisposition to Disease - genetics ; Humans ; Isoenzymes - genetics ; Lymphocytes - metabolism ; Metastasis ; Mosaicism ; Mutation ; Ovarian cancer ; Ovarian Neoplasms - genetics ; Phosphoprotein Phosphatases - genetics ; Protein Phosphatase 2C ; Sequence Analysis, DNA ; Tumor Suppressor Protein p53 - metabolism
É parte de: Nature (London), 2013-01, Vol.493 (7432), p.406-410
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Joint first author
E.R., K.S., P.H., N.W., T-P.Y., M.B., M.C., C.T., J.T., M.Mc., P.De., P.Do. and N.R (chair) are the WTCCC exon-resequencing group who devised and funded Phase 1. J.W.A., J.Ba., J.Be., A.F.B., C.B., G.B., C.C., J.C., R.D., A.D., F.D., D.E., D.G.E., L.G., A.H., L.I., A.K., F.L., Z.M., P.J.M., J.P., M.P., M.T.R., S.Sh., L.W. and N.R. are centre leads of the Breast and Ovarian Cancer Susceptibility Collaboration, which is coordinated by M.W.P and A.Z. A full list of the WTCCC and BOCS consortia are in the Supplementary Material. R.H and M.G assembled the unselected ovarian cancer series. L.G. coordinated Phase 1 sequencing. P.H, M.R. and P.Do. undertook analysis of the pooled DNA repair panel. J.D., A.M., S.Se., S.H. and E.R. undertook NGS sequencing and analysis. S.Se. E.R., S.DVS., N.A.P., A.Re., K.S., C.L. and J.D. undertook Sanger sequencing, MLPA, and tumour microsatellite analysis. E.R. undertook sample selection and data analyses with C.T. A.C.A. wrote the risk analysis software and oversaw the penetrance analysis which was performed by E.R. A.Ri. provided and optimised Platypus. D.N R., A.C-F. and J.S.R-F. undertook histopathological analyses and performed microdissections. I.B., R.B., C.J.L. and A.A. undertook functional analyses. E.R., K.S. and N.R. managed and oversaw all aspects of the study and wrote the manuscript.
Reprints and permissions information is available at www.nature.com/reprints. There are no competing financial interests for any of the authors.
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Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

England: Nature Publishing Group

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