Familial Cancer

, Volume 11, Issue 4, pp 595–600 | Cite as

Identification of a novel NBN truncating mutation in a family with hereditary prostate cancer

  • Kimberly A. ZuhlkeEmail author
  • Anna M. Johnson
  • Linda A. Okoth
  • Elena M. Stoffel
  • Christiane M. Robbins
  • Waibov A. Tembe
  • Claudia A. Salinas
  • S. Lilly Zheng
  • Jianfeng Xu
  • John D. Carpten
  • Ethan M. Lange
  • William B. Isaacs
  • Kathleen A. Cooney
Original Article


Nibrin (NBN), located on chromosome 8q21 is a gene involved in DNA double-strand break repair that has been implicated in the rare autosomal recessive chromosomal instability syndrome known as Nijmegen Breakage Syndrome (NBS). NBS is characterized by specific physical characteristics (microcephaly and dysmorphic facies), immunodeficiency, and increased risk of malignancy. Individuals who are heterozygous for NBN mutations are clinically asymptomatic, but may display an elevated risk for certain cancers including, but not limited to, ovarian and prostate cancer as well as various lymphoid malignancies. In this study, 94 unrelated familial prostate cancer cases from the University of Michigan Prostate Cancer Genetics Project (n = 54) and Johns Hopkins University (n = 40) were subjected to targeted next-generation sequencing of the exons, including UTRs, of NBN. One individual of European descent, diagnosed with prostate cancer at age 52, was identified to have a heterozygous 2117 C > G mutation in exon 14 of the gene, that results in a premature stop at codon 706 (S706X). Sequencing of germline DNA from additional male relatives showed partial co-segregation of the NBN S706X mutation with prostate cancer. This NBN mutation was not observed among 2768 unrelated European men (1859 with prostate cancer and 909 controls). NBN is involved in double-strand break repair as a component of the MRE11 (meiotic recombination 11)/RAD50/NBN genomic stability complex. The S706X mutation truncates the protein in a highly conserved region of NBN near the MRE11 binding site, thus suggesting a role for rare NBN mutations in prostate cancer susceptibility.


Cancer Hereditary Prostate NBN gene 



This work was supported by grants (CA79596, CA136621, and P50 CA69568) from the National Institutes of Health. The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). We also thank the men with prostate cancer and their family members for their participation in this research.


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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Kimberly A. Zuhlke
    • 1
    Email author
  • Anna M. Johnson
    • 1
  • Linda A. Okoth
    • 1
  • Elena M. Stoffel
    • 1
  • Christiane M. Robbins
    • 3
  • Waibov A. Tembe
    • 3
  • Claudia A. Salinas
    • 1
  • S. Lilly Zheng
    • 4
  • Jianfeng Xu
    • 4
  • John D. Carpten
    • 3
  • Ethan M. Lange
    • 5
  • William B. Isaacs
    • 6
  • Kathleen A. Cooney
    • 1
    • 2
  1. 1.Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of UrologyUniversity of Michigan Medical SchoolAnn ArborUSA
  3. 3.Translational Genomics Research InstitutePhoenixUSA
  4. 4.Center for Cancer GenomicsWake Forest University School of MedicineWinston-SalemUSA
  5. 5.University of North Carolina, Lineberger Comprehensive Cancer CenterChapel HillUSA
  6. 6.The Johns Hopkins University, The James Buchanan Brady Urological InstituteBaltimoreUSA

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