Paula Paulo1, Sofia Maia1, Carla Pinto2, Pedro Pinto1, Augusta Monteiro1, Ana Peixoto2, Manuel R. Teixeira1,2,3
1Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal;
2Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal;
3Biomedical Sciences Institute Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
Considering that mutations in known prostate cancer (PrCa) predisposition genes, including those responsible for hereditary breast/ovarian cancer and Lynch syndromes, explain less than 5% of early-onset/familial PrCa, we have sequenced 94 genes associated with cancer predisposition using next generation sequencing (NGS) in a series of 121 PrCa patients.
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We found monoallelic truncating/deleterious mutations in seven genes, including ATM and CHEK2, which have previously been associated with PrCa predisposition, and five new candidate PrCa associated genes involved in cancer predisposing recessive disorders, namely RAD51C, FANCD2, FANCI, CEP57 and RECQL4. Using in silico pathogenicity prediction of missense variants among 18 genes associated with breast/ovarian cancer and/or Lynch syndrome, followed by KASP genotyping in 710 healthy controls, we identified “likely pathogenic” missense variants in ATM, BRIP1, CHEK2 and TP53. In conclusion, this study has identified putative PrCa predisposing germline mutations in 14.9% of early-onset/familial PrCa patients, supporting the usefulness of NGS to unveil the genetic and clinical heterogeneity behind inherited PrCa predisposition.