NBS1 (Nijmegen breakage syndrome 1), located on chromosome 8q21, has been postulated as a prostate cancer (PrCa) susceptibility gene. NBS1, also known as p95, is a tumor suppressor gene that is part of the MRE11/RAD50 double strand break repair complex. Individuals carrying biallelic mutations in NBS1 will generally have microcephaly, facial deformities, mental retardation, impaired immunity, and increased risk to multiple cancers. Numerous mutations have been identified including a founder mutation 657del5, a five base pair deletion in exon 6 leading to a truncated protein. Within a Slavic population, carriers of 657del5 have an increase risk of prostate, colon, rectum, and breast cancer, as well as melanoma and non-Hodgkin lymphoma. Deletion frequency in cases range from 1.3-9.0% while the carrier frequency in a Slavic population is approximately 0.6%. To determine whether mutation 657del5 increases the risk of prostate cancer in a Caucasian North American population, we screened those with a strong family history of PrCa (n=436 from 178 families), those with a reported negative PrCa family history (n=496), and a population-based control (n=492) using an ABI3100 for PCR based fragment analysis. Our controls have been extensively screened for PrCa by digital rectal examination, serum PSA measurement, transrectal sonographic imaging, and when indicated, biopsy. Five individuals were identified as carriers of the 657del5 mutation in our cases; 3 in the familial group and 2 in the sporadic group. None were detected in our control population. Within the familial group, all three affected individuals who carried the mutation originated from the same family, suggesting a causative effect. To help determine if the mutation 657del5 fits a tumor suppressor model, we analyzed tumors from two carriers of 657del5 for LOH; one familial case and one sporadic case. In both cases, the mutant allele was lost leaving the wildtype allele. Overall, these data suggest that the 657del5 mutation within NBS1 plays a limited role in prostate cancer susceptibility within our patient population. Additionally, based on the LOH results, a tumor suppressor model may not apply to NBS1. Other models may have to be considered if NBS1 abnormalities truly increase susceptibility to prostate cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]