An inherited NBN mutation is associated with poor prognosis prostate cancer

Background:To establish the contribution of eight founder alleles in three DNA damage repair genes (BRCA1, CHEK2 and NBS1) to prostate cancer in Poland, and to measure the impact of these variants on survival among patients.Methods:Three thousand seven hundred fifty men with prostate cancer and 3956 cancer-free controls were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA, C61G), four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), and one allele in NBS1 (657del5).Results:The NBS1 mutation was detected in 53 of 3750 unselected cases compared with 23 of 3956 (0.6%) controls (odds ratio (OR)=2.5; P=0.0003). A CHEK2 mutation was seen in 383 (10.2%) unselected cases and in 228 (5.8%) controls (OR=1.9; P<0.0001). Mutation of BRCA1 (three mutations combined) was not associated with the risk of prostate cancer (OR=0.9; P=0.8). In a subgroup analysis, the 4153delA mutation was associated with early-onset (age ⩽60 years) prostate cancer (OR=20.3, P=0.004). The mean follow-up was 54 months. Mortality was significantly worse for carriers of a NBS1 mutation than for non-carriers (HR=1.85; P=0.008). The 5-year survival for men with an NBS1 mutation was 49%, compared with 72% for mutation-negative cases.Conclusion:A mutation in NBS1 predisposes to aggressive prostate cancer. These data are relevant to the prospect of adapting personalised medicine to prostate cancer prevention and treatment.

[1]  David I. Smith,et al.  Mutations in CHEK2 associated with prostate cancer risk. , 2003, American journal of human genetics.

[2]  H. Samaratunga,et al.  Loss of Heterozygosity at the BRCA2 Locus Detected by Multiplex Ligation-Dependent Probe Amplification is Common in Prostate Cancers from Men with a Germline BRCA2 Mutation , 2008, Clinical Cancer Research.

[3]  P Ghadirian,et al.  Rapid progression of prostate cancer in men with a BRCA2 mutation , 2008, British Journal of Cancer.

[4]  H. Samaratunga,et al.  Loss of Heterozygosity at the BRCA 2 Locus Detected byMultiplex Ligation-Dependent ProbeAmplification is Common in Prostate Cancers fromMenwith a Germline BRCA 2 Mutation , 2008 .

[5]  R. Beyth,et al.  Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials , 2010, BMJ : British Medical Journal.

[6]  Hans Joenje,et al.  Biallelic Inactivation of BRCA2 in Fanconi Anemia , 2002, Science.

[7]  J. Carpten,et al.  Germline mutations in HOXB13 and prostate-cancer risk. , 2012, The New England journal of medicine.

[8]  R. S. Maser,et al.  An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele , 2001, Nature Genetics.

[9]  K. Offit,et al.  BRCA Mutations and Risk of Prostate Cancer in Ashkenazi Jews , 2004, Clinical Cancer Research.

[10]  M. Digweed.  Human genetic instability syndromes: single gene defects with increased risk of cancer. , 1993, Toxicology letters.

[11]  B. G. Blijenberg,et al.  Prostate-cancer mortality at 11 years of follow-up. , 2012, The New England journal of medicine.

[12]  Johnson M Liu,et al.  Chromosomal breakage syndromes and the BRCA1 genome surveillance complex. , 2001, Trends in molecular medicine.

[13]  J. Petrini.  The mammalian Mre11-Rad50-nbs1 protein complex: integration of functions in the cellular DNA-damage response. , 1999, American journal of human genetics.

[14]  J. Eyfjörd,et al.  BRCA2 mutation in Icelandic prostate cancer patients , 1997, Journal of Molecular Medicine.

[15]  M. King,et al.  Growth retardation and tumour inhibition by BRCA1 , 1996, Nature Genetics.

[16]  J. Cerhan,et al.  Role of the Nijmegen Breakage Syndrome 1 Gene in Familial and Sporadic Prostate Cancer , 2006, Cancer Epidemiology Biomarkers & Prevention.

[17]  B. Ponder,et al.  Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. , 2003, American journal of human genetics.

[18]  A. Jakubowska,et al.  NBS1 Is a Prostate Cancer Susceptibility Gene , 2004, Cancer Research.

[19]  R. Peto,et al.  Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers: case control study. , 2007, Human molecular genetics.

[20]  Douglas F Easton,et al.  Cancer Incidence in BRCA1 mutation carriers. , 2002, Journal of the National Cancer Institute.

[21]  D. Easton,et al.  Risks of cancer in BRCA1-mutation carriers , 1994, The Lancet.

[22]  Ji-Hoon Lee,et al.  ATM Activation by DNA Double-Strand Breaks Through the Mre11-Rad50-Nbs1 Complex , 2005, Science.

[23]  D. Easton,et al.  Germline BRCA1 mutations increase prostate cancer risk , 2012, British Journal of Cancer.

[24]  D. Easton,et al.  Variation in BRCA1 cancer risks by mutation position. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[25]  A. M. Wolf.  Prostate-cancer mortality after PSA screening. , 2012, The New England journal of medicine.

[26]  M. King,et al.  Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. , 1996, American journal of human genetics.

[27]  A. Jakubowska,et al.  Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  M. King,et al.  Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. , 1998, American journal of human genetics.

[29]  A. Jakubowska,et al.  Breast cancer predisposing alleles in Poland , 2005, Breast Cancer Research and Treatment.

[30]  A. Borkowski,et al.  A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer , 2006, Journal of Medical Genetics.

[31]  P. Hartge,et al.  The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. , 1997, The New England journal of medicine.

[32]  J. Carpten,et al.  Identification of a novel NBN truncating mutation in a family with hereditary prostate cancer , 2012, Familial Cancer.

[33]  S. Fox,et al.  The Dawn of a Revolution in Personalized Lung Cancer Prevention , 2011, Cancer Prevention Research.

[34]  G. Rennert,et al.  Differences in the characteristics of families with BRCA1 and BRCA2 mutations in Israel , 2005, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[35]  Ji-Hoon Lee,et al.  Direct Activation of the ATM Protein Kinase by the Mre11/Rad50/Nbs1 Complex , 2004, Science.

[36]  W. Foulkes,et al.  Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. , 1999, Journal of the National Cancer Institute.

[37]  D. Easton,et al.  Cancer incidence in BRCA1 mutation carriers , 2003 .

[38]  K. Chrzanowska,et al.  Carrier frequency of mutation 657del5 in the NBS1 gene in a population of polish pediatric patients with sporadic lymphoid malignancies , 2006, International journal of cancer.

[39]  Matthias Platzer,et al.  Nibrin, a Novel DNA Double-Strand Break Repair Protein, Is Mutated in Nijmegen Breakage Syndrome , 1998, Cell.

[40]  D. Easton,et al.  Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis , 2010, British Journal of Cancer.

[41]  J. Schleutker,et al.  CHEK2 variants associate with hereditary prostate cancer , 2003, British Journal of Cancer.

[42]  D. Jewell,et al.  Genotype-phenotype analysis of the Crohn’s disease susceptibility haplotype on chromosome 5q31 , 2003, Gut.

[43]  D. Clayton,et al.  Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype–phenotype correlation , 1995, Nature Genetics.

[44]  J. Lubiński,et al.  Cancer risks in first degree relatives of BRCA1 mutation carriers: effects of mutation and proband disease status , 2005, Journal of Medical Genetics.

[45]  J. Eyfjörd,et al.  Study of a single BRCA2 mutation with high carrier frequency in a small population. , 1997, American journal of human genetics.

[46]  Katherine M. Tucker,et al.  Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study , 2011, BJU international.

[47]  E. Seemanová,et al.  Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations , 2000, European Journal of Human Genetics.

[48]  D. Easton,et al.  BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients , 2011, British Journal of Cancer.