Haploinsufficiency in DNA polymerase β increases cancer risk with age and alters mortality rate

This study uses a base excision repair (BER)-deficient model, the DNA polymerase β heterozygous mouse, to investigate the effect of BER deficiency on tumorigenicity and aging. Aged β-pol^+/- mice express 50% less β-pol transcripts and protein (P < 0.05) than aged β-pol^+/+ mice, showing maintenance of the heterozygous state over the life span of the mouse. This reduction in β-pol expression was not associated with an increase in mutation rate but was associated with a 100% increase in the onset of hypoploidy. Aged β-pol^+/- mice exhibited a 6.7-fold increase in developing lymphoma (P < 0.01). Accordingly, 38% of β-pol^+/- mice exhibited lymphoid hyperplasia, whereas none of the β-pol^+/+ exhibited this phenotype. β-pol ^+/- mice were also more likely to develop adenocarcinoma (2.7-fold increase; P < 0.05) and more likely to develop multiple tumors, as 20% of the β-pol^+/- animals died bearing multiple tumors compared with only 5% of the β-pol^+/+ animals (P < 0.05). In spite of accelerated tumor development, no gross effect of β-pol heterozygosity was seen with respect to life span. However, the survival curves for the β-pol^+/+ and β-pol^+/- mice are not identical. A maximum likelihood estimation analysis showed a modest but significant (P < 0.05) acceleration of the age-dependent mortality rate in β-pol ^+/- mice. Thus, the β-pol^+/- mouse represents a model in which mortality rate and tumor development are accelerated and provides evidence supporting the role of genomic maintenance in both aging and carcinogenesis.