Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

POLE mutations in families predisposed to cutaneous melanoma

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Risk of multiple colorectal cancer development depends on age and subgroup in individuals with hereditary predisposition

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Unsolicited information letters to increase awareness of Lynch syndrome and familial colorectal cancer: reactions and attitudes

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. BRCA1/BRCA2 founder mutations and cancer risks: impact in the western Danish population

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. No evidence of increased breast cancer risk for proven noncarriers from BRCA1 and BRCA2 families

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Evaluation of tumor-infiltrating lymphocytes and association with prognosis in BRCA-mutated breast cancer

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Pediatric cancer families' participation in whole-genome sequencing research in Denmark: Parent perspectives

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. En familie med nedarvet DICER1-mutation

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Kræftdisponerende mutationer er hyppige hos børn og unge med kræft

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Is DBCG abreast of new developments?

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Lauren G Aoude
  • Ellen Heitzer
  • Peter Johansson
  • Michael Gartside
  • Karin Wadt
  • Antonia L Pritchard
  • Jane M Palmer
  • Judith Symmons
  • Anne-Marie Gerdes
  • Grant W Montgomery
  • Nicholas G Martin
  • Ian Tomlinson
  • Stephen Kearsey
  • Nicholas K Hayward
View graph of relations

Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol ε mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer.

Original languageEnglish
JournalFamilial Cancer
Volume14
Issue number4
Pages (from-to)621-8
Number of pages8
ISSN1389-9600
DOIs
Publication statusPublished - Dec 2015

ID: 45842782