Familial Cancer

, Volume 18, Issue 2, pp 173–178 | Cite as

Germline mutation p.N363K in POLE is associated with an increased risk of colorectal cancer and giant cell glioblastoma

  • P. Vande Perre
  • A. Siegfried
  • C. Corsini
  • D. Bonnet
  • C. Toulas
  • N. Hamzaoui
  • J. Selves
  • E. Chipoulet
  • J. S. Hoffmann
  • E. Uro-Coste
  • R. GuimbaudEmail author
Short Communication


Germline mutations of the POLE gene are responsible for polymerase proofreading-associated polyposis syndrome (PPAP). These mutations were hypothesised to predispose to extra-gastrointestinal tumours (ovary, endometrium, brain), but this association has not been confirmed so far. We report a family with an autosomal dominant inheritance of PPAP due to a c.1089C>A; p.Asn363Lys mutation in the proofreading exonuclease domain of POLE. Ten patients presenting a history of colorectal tumours and three patients with polyposis are indexed in this family. Three carriers (including siblings and a distant cousin at 30, 45 and 52 respectively) and another member (at 37 not tested) presented glioblastoma. This is the second family reported to carry this mutation. Among the four glioblastomas in the family that we report, both show similar pathology: giant cell glioblastoma. These cases suggest that the c.1089C>A germline POLE mutation may confer an increased risk of brain cancer [incidence 17.4% (4/23) in mutation carriers combining the two families]. More observations are needed to support this hypothesis. It seems that not all mutations of POLE are equally associated with extra-gastrointestinal tumours. Although carriers of a mutation responsible for PPAP should benefit from screening for colorectal and uterine cancer, due to the rapid evolution of glioblastoma the value of neurological follow-up and brain imaging screening remains questionable. Nevertheless, considering the limitations of standard therapy for glioblastoma, mutation status could be useful for targeting therapy. The biological mechanism linking POLE mutation to glioblastoma remains to be determined.


POLE Polymerase epsilon PPAP Proofreading Glioblastoma Giant cells 



We thank patients and patient families for their participation. We thank Doctor François Labrousse (CHU Limoges) for sharing histological data.

Compliance with ethical standards

Competing interests

The authors declare that they have no competing interests.

Supplementary material

10689_2018_102_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 14 KB)


  1. 1.
    Palles C, Cazier J-B, Howarth KM et al (2013) Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 45(2):136–144. CrossRefGoogle Scholar
  2. 2.
    Rayner E, van Gool IC, Palles C et al (2016) A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer 16(2):71–81. CrossRefGoogle Scholar
  3. 3.
    Heitzer E, Tomlinson I (2014) Replicative DNA polymerase mutations in cancer. Curr Opin Genet Dev 24:107–113. CrossRefGoogle Scholar
  4. 4.
    Rohlin A, Zagoras T, Nilsson S et al (2014) A mutation in POLE predisposing to a multi-tumour phenotype. Int J Oncol 45(1):77–81. CrossRefGoogle Scholar
  5. 5.
    Boland CR, Thibodeau SN, Hamilton SR et al (1998) A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58(22):5248–5257Google Scholar
  6. 6.
    Bonnet D, Selves J, Toulas C et al (2012) Simplified identification of Lynch syndrome: a prospective, multicenter study. Dig Liver Dis 44(6):515–522. CrossRefGoogle Scholar
  7. 7.
    Crocetti E, Trama A, Stiller C et al (2012) Epidemiology of glial and non-glial brain tumours in Europe. Eur J Cancer 48(10):1532–1542. CrossRefGoogle Scholar
  8. 8.
    Ostrom QT, Gittleman H, Farah P et al (2013) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncology 15(Suppl 2):ii1–i56. CrossRefGoogle Scholar
  9. 9.
    Bellido F, Pineda M, Aiza G et al (2016) POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet Med 18(4):325–332. CrossRefGoogle Scholar
  10. 10.
    Erson-Omay EZ, Caglayan AO, Schultz N et al (2015) Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis. Neuro Oncology 17(10):1356–1364. CrossRefGoogle Scholar
  11. 11.
    Johanns TM, Miller CA, Dorward IG et al (2016) Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov 6(11):1230–1236. CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Service de Génétique Médicale, Hôpital PurpanCHU de ToulouseToulouseFrance
  2. 2.Oncogénétique, Institut Claudius RegaudIUCT-OncopôleToulouseFrance
  3. 3.Université Toulouse III Paul SabatierToulouseFrance
  4. 4.Département de PathologieCHU de Toulouse, IUCT-OToulouseFrance
  5. 5.Service d’Oncogénétique, Département de Génétique MédicaleCHU de MontpellierMontpellierFrance
  6. 6.Oncologie Digestive: Pôle digestif- IUCT-Rangueil/LarreyCHU de ToulouseToulouseFrance
  7. 7.UMR 1037, CRCTToulouseFrance
  8. 8.Service de Biochimie et Génétique MoléculaireHôpital CochinParisFrance

Personalised recommendations