Is hEXO1 a cancer predisposing gene?

Abstract

The link between hEXO1 and cancer is not obvious, and the literature reveals contradicting and ambiguous results. However, two different hypotheses might explain these contradicting conclusions (Fig. 1). Germ line mutations in hEXO1 are likely to result in a weak mutator phenotype and may predispose the carriers to develop cancer at an advanced age and to possibly display phenotypes not associated with classic HNPCC. Such affected individuals would be diagnosed with sporadic CRC, although a mutation in hEXO1 contributes to the onset of disease. Alternatively, the weak mutator phenotype of hEXO1 mutations becomes robust and thereby pathogenic when combined with either strong or weak mutator alleles of other MMR genes. This multimutation hypothesis for the pathology of hEXO1 mutations may explain the contradicting results described in the literature regarding the relation between hEXO1 and cancer. Finally, hEXO1 may be involved in carcinogenesis through pathways not directly associated with the MMR pathway. One such pathway could be genetic recombination; altered hEXO1 activity may cause genetic instability through perturbation of homologous recombination, repair of DSBs, and/or telomere resection.