DNA polymerase ε deficiency leading to an ultramutator phenotype: A novel clinically relevant entity

Enrico Castellucci, Tianfang He, D. Yitzchak Goldstein, Balazs Halmos, Jennifer Chuy

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Deficiencies in DNA repair due to mutations in the exonuclease domain of DNA polymerase ε have recently been described in a subset of cancers characterized by an ultramutated andmicrosatellite stable (MSS) phenotype. This alteration in DNA repair is distinct from the better-known mismatch repair deficiencies which lead to microsatellite instability (MSI) and an increased tumor mutation burden. Instead, mutations in POLE lead to impaired proofreading intrinsic to Pol ε during DNA replication resulting in a dramatically increased mutation rate. Somatic mutations of Pol ε have been foundmost frequently in endometrial and colorectal cancers (CRC) and can lead to a unique familial syndrome in the case of germlinemutations. While other key genomic abnormalities, such as MSI, have known prognostic and treatment implications, in this case it is less clear. As molecular genotyping of tumors becomes routine in the care of cancer patients, less common, but potentially actionable findings such as these POLE mutations could be overlooked unless appropriate algorithms are in place.We present two cases of metastatic CRC with a POLE mutation, both of which are ultramutated and MSS. The basic biochemical mechanisms leading to a unique phenotype in POLE deficiency as well as challenges faced with interpreting the genomic profiling of tumors in this important subset of patients and the potential clinical implications will be discussed here.

Original languageEnglish (US)
Pages (from-to)497-502
Number of pages6
Issue number5
StatePublished - May 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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