Genetic Epidemiology, Translational Neurogenomics, Psychiatric 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
32716505
TITLE
Multiplex melanoma families are enriched for polygenic risk.
ABSTRACT
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.
DATE PUBLISHED
2020 Jul 27
HISTORY
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
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Law MH Law Matthew H MH Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Aoude LG Aoude Lauren G LG Surgical Oncology Group, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, 4102, Australia.
Duffy DL Duffy David L DL Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Long GV Long Georgina V GV Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia.
Johansson PA Johansson Peter A PA Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Pritchard AL Pritchard Antonia L AL Genetics and Immunology, University of the Highlands and Islands, An Lòchran, 10 Inverness Campus, Inverness, IV2 5NA, United Kingdom.
Khosrotehrani K Khosrotehrani Kiarash K Department of Dermatology, Princess Alexandra Hospital, Brisbane, QLD, 4102, Australia.
Mann GJ Mann Graham J GJ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Montgomery GW Montgomery Grant W GW Molecular Biology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Iles MM Iles Mark M MM Leeds Institute for Medical Research, University of Leeds, Leeds, LS2 9JT, UK.
Cust AE Cust Anne E AE School of Public Health, The University of Sydney, Sydney, NSW, 2006, Australia.
Palmer JM Palmer Jane M JM Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Melanoma GWAS Consortium
Shannon KF Shannon Kerwin F KF Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2050, Australia.
Spillane AJ Spillane Andrew J AJ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2050, Australia.
Stretch JR Stretch Jonathan R JR Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2050, Australia.
Thompson JF Thompson John F JF Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2050, Australia.
Saw RPM Saw Robyn P M RPM Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2050, Australia.
Scolyer RA Scolyer Richard A RA Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, 2050, Australia.
Martin NG Martin Nicholas G NG Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Hayward NK Hayward Nicholas K NK Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
MacGregor S MacGregor Stuart S Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
INVESTIGATORS
JOURNAL
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
MEDLINE JOURNAL
MEDLINETA: Hum Mol Genet
COUNTRY: England
ISSNLINKING: 0964-6906
NLMUNIQUEID: 9208958
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
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