A novel POLE mutation associated with cancers of colon, pancreas, ovaries and small intestine

Fam Cancer. 2015 Sep;14(3):437-48. doi: 10.1007/s10689-015-9803-2.


In some families there is an increased risk for colorectal cancer, caused by heritable, but often unidentified genetic mutations predisposing to the disease. We have identified the likely genetic cause for disease predisposition in a large family with high burden of colorectal adenomas and carcinomas, in addition to extra-colonic cancers. This family had previously been tested for known cancer susceptibility genes, with negative results. Exome sequencing was used to identify a novel mutation, c.1373A>T (p.Tyr458Phe), in the gene for DNA polymerase epsilon catalytic subunit (POLE). This mutation is located in the active site of the exonuclease domain of the enzyme, and affects a residue that has previously been shown to be important for exonuclease activity. The first predisposing mutation identified in POLE (c.1270C>G, p.Leu424Val) was associated with colorectal cancer only, but another mutation with a broader tumour spectrum (c.1089C>A, p.Asn363Lys) has recently been reported. In the family described in the present study, carriers generally have multiple colorectal adenomas and cancer of colon, pancreas, ovaries and small intestine which represents an important broadening of the tumour spectrum of POLE mutation carriers. We also observe a large phenotypic variation among the POLE mutation carriers in this family, most likely explained by modifying variants in other genes. One POLE mutation carrier has a novel variant in EXO1 (c.458C>T, p.Ala153Val), which may contribute to a more severe phenotype. The findings in this study will have important implications for risk assessment and surveillance of POLE mutation carriers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Colorectal Neoplasms / genetics*
  • DNA Polymerase II / genetics*
  • DNA Polymerase II / metabolism
  • Exome
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Intestine, Small / pathology
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Ovarian Neoplasms / genetics*
  • Pancreatic Neoplasms / genetics*
  • Pedigree
  • Poly-ADP-Ribose Binding Proteins
  • Sequence Homology, Amino Acid


  • Poly-ADP-Ribose Binding Proteins
  • DNA Polymerase II
  • POLE protein, human