Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer

PLoS Genet. 2018 Apr 16;14(4):e1007355. doi: 10.1371/journal.pgen.1007355. eCollection 2018 Apr.

Abstract

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. We found monoallelic truncating/functionally 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. Furthermore, 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. Further data will be necessary to confirm the genetic heterogeneity of inherited PrCa predisposition hinted in this study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Breast Neoplasms / genetics
  • Case-Control Studies
  • Checkpoint Kinase 2 / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • Computer Simulation
  • DNA-Binding Proteins / genetics
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Fanconi Anemia Complementation Group Proteins / genetics
  • Female
  • Genes, p53
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Germ-Line Mutation*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Microtubule-Associated Proteins / genetics
  • Middle Aged
  • Mutation, Missense
  • Nuclear Proteins / genetics
  • Ovarian Neoplasms / genetics
  • Pedigree
  • Prostatic Neoplasms / genetics*
  • RNA Helicases / genetics
  • RecQ Helicases / genetics
  • Sequence Analysis, DNA

Substances

  • CEP57 protein, human
  • DNA-Binding Proteins
  • FANCD2 protein, human
  • FANCI protein, human
  • Fanconi Anemia Complementation Group D2 Protein
  • Fanconi Anemia Complementation Group Proteins
  • Microtubule-Associated Proteins
  • Nuclear Proteins
  • RAD51C protein, human
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human
  • RECQL4 protein, human
  • RecQ Helicases
  • BRIP1 protein, human
  • RNA Helicases

Supplementary concepts

  • Prostate cancer, familial

Grant support

We thank the funding support from Portuguese Oncology Institute of Porto Research Center (CI-IPOP-16-2012) and from Fundação para a Ciência e a Tecnologia (FCT; PEst-OE/SAU/UI0776/2014 and PTDC/DTP-PIC/1308/2014). The following authors were awarded with grants from FCT: PPa (UID/DTP/00776/2013/POCI-01-0145-FEDER-006868), SM (SFRH/BD/71397/2010) and PPi (SFRH/BD/73719/2010). AM was funded by Portuguese League Against Cancer (Liga Portuguesa Contra o Cancro - Núcleo Regional do Norte). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.