title: Truncating and missense PPM1D mutations in early-onset and/or familial/hereditary prostate cancer patients.
abstract: Truncating activating mutations in the last exon of PPM1D have been described in patients with breast, ovarian, colorectal and non-small cell lung cancer, but recent data indicate that they may be associated with previous chemotherapy. In this study we evaluated the prevalence of PPM1D mutations in white blood cells (WBC) of 462 patients with early-onset and/or familial/hereditary prostate cancer (PrCa) by sequencing the coding region of exon 6. Two truncating mutations were found in two patients (0.4%), both treated with androgen-ablation therapy but no chemotherapy prior to blood collection. Next generation sequencing analysis showed that the truncating variants were present in 21.4% and 32.4% of the reads, indicating that they were in mosaic in WBC, something that was confirmed by its absence in a different tissue from one of these patients. Additionally, nine patients (1.95%) were found to harbor non-synonymous germline mutations, with three patients sharing the same missense variant, c.1607G > A, p.Arg536Lys. This variant was predicted to be deleterious by different in silico tools and was not found in the 293 male control subjects tested. Large cohorts and/or functional evaluation are needed to clarify the nature of the truncating mosaic mutations in PrCa patients treated with and without androgen-ablation therapy and to evaluate the contribution of the recurrent missense variant to the risk of developing PrCa. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Cardoso
authors.affiliation: Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Paulo
authors.affiliation: Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Maia
authors.affiliation: Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal. manuel.teixeira@ipoporto.min-saude.pt.|Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal. manuel.teixeira@ipoporto.min-saude.pt.|Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal. manuel.teixeira@ipoporto.min-saude.pt.
authors.forename: Manuel R
authors.identifier: 0000-0002-4896-5982
authors.initials: MR
authors.lastname: Teixeira
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D017668:Age of Onset; D014408:Biomarkers, Tumor / Q000235:genetics*; D002280:Basal Cell Carcinoma / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D000071636:Protein Phosphatase 2C / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C000607458:PPM1D protein, human; D000071636:Protein Phosphatase 2C