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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

Abstract

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.

Keywords

Cancer Hereditary Prostate NBN gene 

Notes

Acknowledgments

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.

References

  1. 1.
    Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29. doi: 10.3322/caac.20138 PubMedCrossRefGoogle Scholar
  2. 2.
    Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC (1992) Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 89(8):3367–3371PubMedCrossRefGoogle Scholar
  3. 3.
    Schaid DJ, McDonnell SK, Blute ML, Thibodeau SN (1998) Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62(6):1425–1438. doi: 10.1086/301862 PubMedCrossRefGoogle Scholar
  4. 4.
    Gronberg H, Damber L, Damber JE, Iselius L (1997) Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am J Epidemiol 146(7):552–557PubMedCrossRefGoogle Scholar
  5. 5.
    Smith JR, Freije D, Carpten JD, Gronberg H, Xu J, Isaacs SD, Brownstein MJ, Bova GS, Guo H, Bujnovszky P, Nusskern DR, Damber JE, Bergh A, Emanuelsson M, Kallioniemi OP, Walker-Daniels J, Bailey-Wilson JE, Beaty TH, Meyers DA, Walsh PC, Collins FS, Trent JM, Isaacs WB (1996) Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274(5291):1371–1374PubMedCrossRefGoogle Scholar
  6. 6.
    Xu J, Meyers D, Freije D, Isaacs S, Wiley K, Nusskern D, Ewing C, Wilkens E, Bujnovszky P, Bova GS, Walsh P, Isaacs W, Schleutker J, Matikainen M, Tammela T, Visakorpi T, Kallioniemi OP, Berry R, Schaid D, French A, McDonnell S, Schroeder J, Blute M, Thibodeau S, Gronberg H, Emanuelsson M, Damber JE, Bergh A, Jonsson BA, Smith J, Bailey-Wilson J, Carpten J, Stephan D, Gillanders E, Amundson I, Kainu T, Freas-Lutz D, Baffoe-Bonnie A, Van Aucken A, Sood R, Collins F, Brownstein M, Trent J (1998) Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 20(2):175–179. doi: 10.1038/2477 PubMedCrossRefGoogle Scholar
  7. 7.
    Berry R, Schroeder JJ, French AJ, McDonnell SK, Peterson BJ, Cunningham JM, Thibodeau SN, Schaid DJ (2000) Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am J Hum Genet 67(1):82–91. doi: 10.1086/302994 PubMedCrossRefGoogle Scholar
  8. 8.
    Thomas G, Jacobs KB, Yeager M, Kraft P, Wacholder S, Orr N, Yu K, Chatterjee N, Welch R, Hutchinson A, Crenshaw A, Cancel-Tassin G, Staats BJ, Wang Z, Gonzalez-Bosquet J, Fang J, Deng X, Berndt SI, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cussenot O, Valeri A, Andriole GL, Crawford ED, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover R, Hayes RB, Hunter DJ, Chanock SJ (2008) Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 40(3):310–315. doi: 10.1038/ng.91 PubMedCrossRefGoogle Scholar
  9. 9.
    Eeles RA, Kote-Jarai Z, Al Olama AA, Giles GG, Guy M, Severi G, Muir K, Hopper JL, Henderson BE, Haiman CA, Schleutker J, Hamdy FC, Neal DE, Donovan JL, Stanford JL, Ostrander EA, Ingles SA, John EM, Thibodeau SN, Schaid D, Park JY, Spurdle A, Clements J, Dickinson JL, Maier C, Vogel W, Dork T, Rebbeck TR, Cooney KA, Cannon-Albright L, Chappuis PO, Hutter P, Zeegers M, Kaneva R, Zhang HW, Lu YJ, Foulkes WD, English DR, Leongamornlert DA, Tymrakiewicz M, Morrison J, Ardern-Jones AT, Hall AL, O’Brien LT, Wilkinson RA, Saunders EJ, Page EC, Sawyer EJ, Edwards SM, Dearnaley DP, Horwich A, Huddart RA, Khoo VS, Parker CC, Van As N, Woodhouse CJ, Thompson A, Christmas T, Ogden C, Cooper CS, Southey MC, Lophatananon A, Liu JF, Kolonel LN, Le Marchand L, Wahlfors T, Tammela TL, Auvinen A, Lewis SJ, Cox A, FitzGerald LM, Koopmeiners JS, Karyadi DM, Kwon EM, Stern MC, Corral R, Joshi AD, Shahabi A, McDonnell SK, Sellers TA, Pow-Sang J, Chambers S, Aitken J, Gardiner RA, Batra J, Kedda MA, Lose F, Polanowski A, Patterson B, Serth J, Meyer A, Luedeke M, Stefflova K, Ray AM, Lange EM, Farnham J, Khan H, Slavov C, Mitkova A, Cao G, Easton DF (2009) Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat Genet 41(10):1116–1121. doi: 10.1038/ng.450 PubMedCrossRefGoogle Scholar
  10. 10.
    Kote-Jarai Z, Olama AA, Giles GG, Severi G, Schleutker J, Weischer M, Campa D, Riboli E, Key T, Gronberg H, Hunter DJ, Kraft P, Thun MJ, Ingles S, Chanock S, Albanes D, Hayes RB, Neal DE, Hamdy FC, Donovan JL, Pharoah P, Schumacher F, Henderson BE, Stanford JL, Ostrander EA, Sorensen KD, Dork T, Andriole G, Dickinson JL, Cybulski C, Lubinski J, Spurdle A, Clements JA, Chambers S, Aitken J, Gardiner RA, Thibodeau SN, Schaid D, John EM, Maier C, Vogel W, Cooney KA, Park JY, Cannon-Albright L, Brenner H, Habuchi T, Zhang HW, Lu YJ, Kaneva R, Muir K, Benlloch S, Leongamornlert DA, Saunders EJ, Tymrakiewicz M, Mahmud N, Guy M, O’Brien LT, Wilkinson RA, Hall AL, Sawyer EJ, Dadaev T, Morrison J, Dearnaley DP, Horwich A, Huddart RA, Khoo VS, Parker CC, Van As N, Woodhouse CJ, Thompson A, Christmas T, Ogden C, Cooper CS, Lophatonanon A, Southey MC, Hopper JL, English DR, Wahlfors T, Tammela TL, Klarskov P, Nordestgaard BG, Roder MA, Tybjaerg-Hansen A, Bojesen SE, Travis R, Canzian F, Kaaks R, Wiklund F, Aly M, Lindstrom S, Diver WR, Gapstur S, Stern MC, Corral R, Virtamo J, Cox A, Haiman CA, Le Marchand L, Fitzgerald L, Kolb S, Kwon EM, Karyadi DM, Orntoft TF, Borre M, Meyer A, Serth J, Yeager M, Berndt SI, Marthick JR, Patterson B, Wokolorczyk D, Batra J, Lose F, McDonnell SK, Joshi AD, Shahabi A, Rinckleb AE, Ray A, Sellers TA, Lin HY, Stephenson RA, Farnham J, Muller H, Rothenbacher D, Tsuchiya N, Narita S, Cao GW, Slavov C, Mitev V, Easton DF, Eeles RA (2011) Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nat Genet 43(8):785–791. doi: 10.1038/ng.882ng.882 PubMedCrossRefGoogle Scholar
  11. 11.
    Weemaes CM, Hustinx TW, Scheres JM, van Munster PJ, Bakkeren JA, Taalman RD (1981) A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatr Scand 70(4):557–564PubMedCrossRefGoogle Scholar
  12. 12.
    Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanova E, Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti RA, Wilson RK, Digweed M, Rosenthal A, Sperling K, Concannon P, Reis A (1998) Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93(3):467–476. doi: S0092-8674(00)81174-5 PubMedCrossRefGoogle Scholar
  13. 13.
    Antoccia A, Kobayashi J, Tauchi H, Matsuura S, Komatsu K (2006) Nijmegen breakage syndrome and functions of the responsible protein, NBS1. Genome Dyn 1:191–205. doi: 10.1159/000092508 PubMedCrossRefGoogle Scholar
  14. 14.
    Seemanova E (1990) An increased risk for malignant neoplasms in heterozygotes for a syndrome of microcephaly, normal intelligence, growth retardation, remarkable facies, immunodeficiency and chromosomal instability. Mutat Res 238(3):321–324PubMedCrossRefGoogle Scholar
  15. 15.
    Ewing CM, Ray AM, Lange EM, Zuhlke KA, Robbins CM, Tembe WD, Wiley KE, Isaacs SD, Johng D, Wang Y, Bizon C, Yan G, Gielzak M, Partin AW, Shanmugam V, Izatt T, Sinari S, Craig DW, Zheng SL, Walsh PC, Montie JE, Xu J, Carpten JD, Isaacs WB, Cooney KA (2012) Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 366(2):141–149. doi: 10.1056/NEJMoa1110000 PubMedCrossRefGoogle Scholar
  16. 16.
    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R (2009) The sequence alignment/map format and SAMtools. Bioinformatics 25(16):2078–2079. doi: 10.1093/bioinformatics/btp352 PubMedCrossRefGoogle Scholar
  17. 17.
    Cybulski C, Gorski B, Debniak T, Gliniewicz B, Mierzejewski M, Masojc B, Jakubowska A, Matyjasik J, Zlowocka E, Sikorski A, Narod SA, Lubinski J (2004) NBS1 is a prostate cancer susceptibility gene. Cancer Res 64(4):1215–1219PubMedCrossRefGoogle Scholar
  18. 18.
    Hebbring SJ, Fredriksson H, White KA, Maier C, Ewing C, McDonnell SK, Jacobsen SJ, Cerhan J, Schaid DJ, Ikonen T, Autio V, Tammela TL, Herkommer K, Paiss T, Vogel W, Gielzak M, Sauvageot J, Schleutker J, Cooney KA, Isaacs W, Thibodeau SN (2006) Role of the Nijmegen breakage syndrome 1 gene in familial and sporadic prostate cancer. Cancer Epidemiol Biomarkers Prev 15(5):935–938. doi: 10.1158/1055-9965.EPI-05-0910 PubMedCrossRefGoogle Scholar
  19. 19.
    Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, Hays L, Morgan WF, Petrini JH (1998) The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93(3):477–486. doi: S0092-8674(00)81175-7 PubMedCrossRefGoogle Scholar
  20. 20.
    Bork P, Hofmann K, Bucher P, Neuwald AF, Altschul SF, Koonin EV (1997) A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins. Faseb J 11(1):68–76PubMedGoogle Scholar
  21. 21.
    Callebaut I, Mornon JP (1997) From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair. FEBS Lett 400(1):25–30. doi: S0014-5793(96)01312-9 PubMedCrossRefGoogle Scholar
  22. 22.
    Becker E, Meyer V, Madaoui H, Guerois R (2006) Detection of a tandem BRCT in Nbs1 and Xrs2 with functional implications in the DNA damage response. Bioinformatics 22(11):1289–1292. doi: 10.1093/bioinformatics/btl075 PubMedCrossRefGoogle Scholar
  23. 23.
    Lim DS, Kim ST, Xu B, Maser RS, Lin J, Petrini JH, Kastan MB (2000) ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature 404(6778):613–617. doi: 10.1038/35007091 PubMedCrossRefGoogle Scholar
  24. 24.
    Desai-Mehta A, Cerosaletti KM, Concannon P (2001) Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization. Mol Cell Biol 21(6):2184–2191. doi: 10.1128/MCB.21.6.2184-2191.2001 PubMedCrossRefGoogle Scholar
  25. 25.
    Falck J, Coates J, Jackson SP (2005) Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434(7033):605–611. doi: 10.1038/nature03442 PubMedCrossRefGoogle Scholar
  26. 26.
    Bennardo N, Stark JM (2010) ATM limits incorrect end utilization during non-homologous end joining of multiple chromosome breaks. PLoS Genet 6(11):e1001194. doi: 10.1371/journal.pgen.1001194 PubMedCrossRefGoogle Scholar
  27. 27.
    Berger AH, Pandolfi PP (2011) Haplo-insufficiency: a driving force in cancer. J Pathol 223(2):137–146. doi: 10.1002/path.2800 PubMedCrossRefGoogle Scholar
  28. 28.
    Liede A, Karlan BY, Narod SA (2004) Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 22(4):735–742. doi: 10.1200/JCO.2004.05.055JCO.2004.05.055 PubMedCrossRefGoogle Scholar
  29. 29.
    Kote-Jarai Z, Jugurnauth S, Mulholland S, Leongamornlert DA, Guy M, Edwards S, Tymrakiewitcz M, O’Brien L, Hall A, Wilkinson R, Al Olama AA, Morrison J, Muir K, Neal D, Donovan J, Hamdy F, Easton DF, Eeles R (2009) A recurrent truncating germline mutation in the BRIP1/FANCJ gene and susceptibility to prostate cancer. Br J Cancer 100(2):426–430. doi: 10.1038/sj.bjc.6604847 PubMedCrossRefGoogle Scholar
  30. 30.
    Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134. doi: 10.1056/NEJMoa0900212 PubMedCrossRefGoogle Scholar

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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