POLE Mutation Detection by SNaPshot

The DNA replicase Pol ε is essential for DNA replication fidelity and the maintenance of genomic stability. Specifically, POLE encodes one of the major catalytic subunits of the DNA Polymerase Epsilon complex and plays a critical role in DNA replication, including proofreading newly synthesized DNA strands and catalyzing 3’-5’ exonuclease activity in the event of any base misincorporations. In addition, POLE has also been implicated in base excision repair, nucleotide excision repair, MMR, double strand break repair, cell checkpoint regulation and propagation of chromatin modification states (Rayer et al. 2016).

Somatic mutations in the proofreading exonuclease domain of the POLE gene have been identified in multiple tumor types and cause an 'ultramutation' phenotype secondary to dysfunctional proofreading and a high rate of base substitution mutation from replicative error. Deleterious mutations in the proofreading exonuclease domain of POLE occur in approximately 7-12% of endometrial carcinomas, 1-2% of colorectal carcinomas and a small number of other cancer types including ovarian, pancreas, stomach, brain, and breast cancers. Of note, several germline POLE mutations have also been identified and are associated with an increased risk of several cancer types (Rayer et al. 2016).

Identifying pathogenic mutations in the POLE gene is clinically important as such mutations are associated with a more favorable prognosis and can impact oncologic management (Church et al. 2015, TCGA 2013). Importantly, POLE mutated tumors may also be eligible for immunotherapy (e.g. check-point inhibitors) given the strong correlation between these mutations and high tumor mutation burden (Mehnert et al. 2016). In addition, several POLE-mutant cancers display increased tumor infiltrating lymphocyte density, a phenotype which also portends better tumor immune response to immunotherapy.