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NBS1 Is a Prostate Cancer Susceptibility Gene

C. Cybulski¹, B. Górski¹, T. Dbniak¹, B. Gliniewicz², M. Mierzejewski¹, B. Masoj¹, A. Jakubowska¹, J. Matyjasik¹, E. Zowocka¹, A. Sikorski², S. A. Narod³ and J. Lubiski¹

¹ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; ² Clinic of Urology, Pomeranian Academy of Medicine, Szczecin, Poland; and ³ Centre for Research in Women’s Health, Toronto, Ontario, Canada

To evaluate whether an inactivating mutation in the gene for the Nijmegen breakage syndrome (NBS1) plays a role in the etiology of prostate cancer, we compared the prevalence of the 657del5 NBS1 founder allele in 56 patients with familial prostate cancer, 305 patients with nonfamilial prostate cancer, and 1500 control subjects from Poland. Loss of heterozygosity analysis also was performed on DNA samples isolated from 17 microdissected prostate cancers, including 8 from carriers of the 657del5 mutation. The NBS1 founder mutation was present in 5 of 56 (9%) patients with familial prostate cancer (odds ratio, 16; P < 0.0001), 7 of 305 (2.2%) patients with nonfamilial prostate cancer (odds ratio, 3.9; P = 0.01), and 9 of 1500 control subjects (0.6%). The wild-type NBS1 allele was lost in seven of eight prostate tumors from carriers of the 657del5 allele, but loss of heterozygosity was seen in only one of nine tumors from noncarriers (P = 0.003). These findings suggest that heterozygous carriers of the NBS1 founder mutation exhibit increased susceptibility to prostate cancer and that the cancers that develop in the prostates of carriers are functionally homozygous for the mutation.

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