NBN – Prostate Cancer

Multiple independent case–control studies have identified heterozygous loss‐of‐function variants in NBN as risk factors for Prostate Cancer. The most prevalent founder allele, c.657_661del (p.Lys219fsTer), was found in 5 of 56 familial cases versus 9 of 1500 controls (odds ratio, 16; P < 0.0001) (PMID:14973119). Sporadic cases also showed enrichment, with 7 of 305 carriers (odds ratio, 3.9; P = 0.01) compared to controls (PMID:14973119).

A large Polish cohort of 3,750 unselected prostate cancer patients and 3,956 controls confirmed the association: 53 carriers among cases versus 23 in controls (OR = 2.5; P = 0.0003) (PMID:23149842). Loss of the wild-type allele was observed in seven of eight tumors from heterozygotes, providing somatic second-hit evidence supporting a tumor suppressor mechanism (PMID:14973119). No significant family segregation data have been reported to date.

Inheritance of prostate cancer risk due to NBN variants follows an autosomal dominant pattern with reduced penetrance; carriers are at moderately elevated risk but do not invariably develop disease. To date, no additional recurrent or founder variants beyond c.657_661del (p.Lys219fsTer) have been linked to prostate cancer in these cohorts.

Functional studies demonstrate that heterozygous c.657_661del carriers experience loss of heterozygosity in tumors, consistent with Knudson’s two-hit model. Nibrin interacts with the MRE11–RAD50 complex in DNA double‐strand break repair, and ATM‐dependent phosphorylation at Ser343 is disrupted in NBS1‐deficient contexts, highlighting impaired DNA damage response as a pathogenic mechanism.

Conflicting evidence arises from smaller series that did not observe an increased 657del5 frequency in hereditary prostate cancer families outside Slavic populations, suggesting population-specific effects and variable penetrance. Nevertheless, the consistent enrichment in large case–control cohorts and demonstration of LOH in tumors argue against a chance association.

In summary, heterozygous truncating variants in NBN, notably c.657_661del (p.Lys219fsTer), confer a moderate but significant increase in prostate cancer risk, supported by robust epidemiological and somatic second-hit data. Incorporation of NBN testing may refine risk stratification in high-risk men.

References

• Cancer research • 2004 • NBS1 is a prostate cancer susceptibility gene. PMID:14973119
• British journal of cancer • 2013 • An inherited NBN mutation is associated with poor prognosis prostate cancer. PMID:23149842

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