Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
26251183
TITLE
POLE mutations in families predisposed to cutaneous melanoma.
ABSTRACT
NlmCategory: UNASSIGNED
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.
DATE PUBLISHED
2015 Aug 7
HISTORY
PUBSTATUS PUBSTATUSDATE
entrez 2015/08/08 06:00
pubmed 2015/08/08 06:00
medline 2015/08/08 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Aoude LG Aoude Lauren G LG QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia, Lauren.Aoude@qimrberghofer.edu.au.
Heitzer E Heitzer Ellen E
Johansson P Johansson Peter P
Gartside M Gartside Michael M
Wadt K Wadt Karin K
Pritchard AL Pritchard Antonia L AL
Palmer JM Palmer Jane M JM
Symmons J Symmons Judith J
Gerdes AM Gerdes Anne-Marie AM
Montgomery GW Montgomery Grant W GW
Martin NG Martin Nicholas G NG
Tomlinson I Tomlinson Ian I
Kearsey S Kearsey Stephen S
Hayward NK Hayward Nicholas K NK
INVESTIGATORS
JOURNAL
VOLUME:
ISSUE:
TITLE: Familial cancer
ISOABBREVIATION: Fam. Cancer
YEAR: 2015
MONTH: Aug
DAY: 7
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1573-7292
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Fam Cancer
COUNTRY: Netherlands
ISSNLINKING: 1389-9600
NLMUNIQUEID: 100898211
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
JOURNAL ARTICLE
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