Increased cancer risk of heterozygotes with NBS1 founder mutation
The chromosomal instability disorder Nijmegen Breakage Syndrome (NBS1) is associated with extreme susceptibility to lymphoid malignancies due to a defect in DNA double strand break repair. Over 90% of NBS patients are homozygous for a founder mutation. This situation offers unique prerequisites for epidemiological studies. We have obtained information on cancer manifestation and mortality of 1806 relatives of 27 homozygous NBS index cases. In addition, we have performed a cohort study, based on detailed medical histories of 344 individuals who were identified through the index cases and recruited without prior knowledge of their carrier status (index-test method). The results show that the cancer risk is highly correlated with the probability of being a carrier. 2. The groups of the cohort study showed no relevant differences in age distribution, socioeconomic status or general medical history. There was a significant difference in the cancer risk between carriers and noncarriers (p < 0.001) which is especially pronounced for the 45 – 60 year old age group. 3. Amongst the grandparents with complete ascertainment, the 28 carriers have developed 10 cancers, the noncarriers, only one (p < 0.001). 4. The NBS carriers show a high disposition for solid tumours. 5. The higher mortality of NBS carriers is reflected in a reduction in the 657del5 mutation frequency in Czechia among older individuals (> 70 years). Thus, the general risk for cancer in NBS1 mutation carriers is substantially elevated. It is clearly higher than in all other chromosomal instability disorders.