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| PMID |
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| TITLE |
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| Multiplex melanoma families are enriched for polygenic risk. |
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| ABSTRACT |
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| Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental aetiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families and the causes of familial clustering in the remainder is unknown. We hypothesise that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni corrected t-test P = 1.5 × 10-5 and 6.3 × 10-45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate new high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect. |
| © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2020/02/18 |
| revised |
2020/07/10 |
| accepted |
2020/07/14 |
| entrez |
2020/07/28 06:00 |
| pubmed |
2020/07/28 06:00 |
| medline |
2020/07/28 06:00 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Law MH |
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Law |
Matthew H |
MH |
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Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
| Aoude LG |
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Aoude |
Lauren G |
LG |
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Surgical Oncology Group, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, 4102, Australia. |
| Duffy DL |
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Duffy |
David L |
DL |
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Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
| Long GV |
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Long |
Georgina V |
GV |
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Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia. |
| Johansson PA |
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Johansson |
Peter A |
PA |
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Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
| Pritchard AL |
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Pritchard |
Antonia L |
AL |
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Genetics and Immunology, University of the Highlands and Islands, An Lòchran, 10 Inverness Campus, Inverness, IV2 5NA, United Kingdom. |
| Khosrotehrani K |
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Khosrotehrani |
Kiarash |
K |
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Department of Dermatology, Princess Alexandra Hospital, Brisbane, QLD, 4102, Australia. |
| Mann GJ |
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Mann |
Graham J |
GJ |
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Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
| Montgomery GW |
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Montgomery |
Grant W |
GW |
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Molecular Biology, The University of Queensland, Brisbane, QLD, 4072, Australia. |
| Iles MM |
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Iles |
Mark M |
MM |
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Leeds Institute for Medical Research, University of Leeds, Leeds, LS2 9JT, UK. |
| Cust AE |
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Cust |
Anne E |
AE |
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School of Public Health, The University of Sydney, Sydney, NSW, 2006, Australia. |
| Palmer JM |
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Palmer |
Jane M |
JM |
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Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
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Melanoma GWAS Consortium |
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| Shannon KF |
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Shannon |
Kerwin F |
KF |
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Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2050, Australia. |
| Spillane AJ |
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Spillane |
Andrew J |
AJ |
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Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2050, Australia. |
| Stretch JR |
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Stretch |
Jonathan R |
JR |
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Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2050, Australia. |
| Thompson JF |
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Thompson |
John F |
JF |
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Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2050, Australia. |
| Saw RPM |
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Saw |
Robyn P M |
RPM |
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Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2050, Australia. |
| Scolyer RA |
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Scolyer |
Richard A |
RA |
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Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, 2050, Australia. |
| Martin NG |
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Martin |
Nicholas G |
NG |
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Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
| Hayward NK |
|
Hayward |
Nicholas K |
NK |
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Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
| MacGregor S |
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MacGregor |
Stuart |
S |
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Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
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| INVESTIGATORS |
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| JOURNAL |
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| VOLUME: |
| ISSUE: |
| TITLE: Human molecular genetics |
| ISOABBREVIATION: Hum. Mol. Genet. |
| YEAR: 2020 |
| MONTH: Jul |
| DAY: 27 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1460-2083 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: Hum Mol Genet |
| COUNTRY: England |
| ISSNLINKING: 0964-6906 |
| NLMUNIQUEID: 9208958 |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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