Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer

Background & Aims: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder caused by familial mutations in some of the genes responsible for DNA mismatch repair. Mutations in the MLH1, MSH2, and MSH6 genes have been documented in this disorder, but there have been limited and conflicting data about the role of another mismatch repair gene, PMS2. It has recently been suggested that mutations in the PMS2 gene do not cause an autosomal dominant disorder. In addition, mutations in each of these 4 mismatch repair genes have been shown to cause an autosomal recessive cancer syndrome in children that is; distinct from hereditary nonpolyposis colorectal cancer. We reviewed a cohort of patients for evidence of an autosomal dominant disorder caused by a mutation in the PMS2 gene. Methods: A cohort of tumor samples from patients with features suggestive of HNPCC was tested for microsatellite instability, the molecular hallmark of HNPCC, and exclusive loss of expression of the PMS2 gene in tumor tissue. Results: A kindred was identified with autosomal dominant HNPCC due to a familial loss-of-function mutation in the PMS2 gene. This is the first description of such a kindred. Conclusion: Mutations in the PMS2 gene can, like mutations in other mismatch repair genes, cause both autosomal dominant HNPCC in adults and an autosomal recessive cancer syndrome in children.