Biallelic mutations in the NBN gene are responsible for the Nijmegen
breakage syndrome (NBS), a rare autosomal recessive disorder characterized by
chromosome instability and hypersensitivity to ionising radiation (IR). Epidemiological
data evidence that the NBN gene can be considered a susceptibility factor for cancer
development, as demonstrated by the fact that almost 40% of NBS patients have
developed a malignancy before the age of 21. Interestingly, also NBN heterozygotes,
which are clinically asymptomatic, display an elevated risk to develop some types of
malignant tumours, especially breast, prostate and colorectal cancers, lymphoblastic
leukaemia, and non-Hodgkin’s lymphoma (NHL). So far, nine mutations in the NBN
gene have been found, at the heterozygous state, in cancer patients. Among them, the
657del5, the I171V and the R215W mutations are the most frequently described. The
pathogenicity of these mutations is presumably connected with their occurrence in the
highly conserved BRCT tandem domains of the NBN protein, which are present in a
large superfamily of proteins and are recognized as major mediators of processes related
to cell-cycle checkpoints and DNA repair. This review will focus on the current stateof-
knowledge regarding the correlation between carriers of NBN gene mutations and the
proneness to the development of malignant tumours.
Keywords: NBN, nijmegen breakage syndrome, NBN carriers, 657del5 founder
mutation, R215W, I171V, BRCT domain, DNA repair.