POLE mutations in families predisposed to cutaneous melanoma

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

doi:10.1007/s10689-015-9826-8

POLE mutations in families predisposed to cutaneous melanoma

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

Department of Clinical Medicine

28 Citations (Scopus)

Abstract

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 language	English
Journal	Familial Cancer
Volume	14
Issue number	4
Pages (from-to)	621-8
Number of pages	8
ISSN	1389-9600
DOIs	https://doi.org/10.1007/s10689-015-9826-8
Publication status	Published - 7 Aug 2015

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title = "POLE mutations in families predisposed to cutaneous melanoma",

abstract = "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.",

author = "Aoude, {Lauren G} and Ellen Heitzer and Peter Johansson and Michael Gartside and Karin Wadt and Pritchard, {Antonia L} and Palmer, {Jane M} and Judith Symmons and Anne-Marie Gerdes and Montgomery, {Grant W} and Martin, {Nicholas G} and Ian Tomlinson and Stephen Kearsey and Hayward, {Nicholas K}",

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T1 - POLE mutations in families predisposed to cutaneous melanoma

AU - Aoude, Lauren G

AU - Heitzer, Ellen

AU - Johansson, Peter

AU - Gartside, Michael

AU - Wadt, Karin

AU - Pritchard, Antonia L

AU - Palmer, Jane M

AU - Symmons, Judith

AU - Gerdes, Anne-Marie

AU - Montgomery, Grant W

AU - Martin, Nicholas G

AU - Tomlinson, Ian

AU - Kearsey, Stephen

AU - Hayward, Nicholas K

PY - 2015/8/7

Y1 - 2015/8/7

N2 - 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.

AB - 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.

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DO - 10.1007/s10689-015-9826-8

M3 - Journal article

C2 - 26251183

SN - 1389-9600

VL - 14

SP - 621

EP - 628

JO - Familial Cancer

JF - Familial Cancer

IS - 4

ER -

POLE mutations in families predisposed to cutaneous melanoma

Abstract

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