Multiplex melanoma families are enriched for polygenic risk

Abstract Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological 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-p...

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Veröffentlicht in:Human molecular genetics 2020-10, Vol.29 (17), p.2976-2985
Hauptverfasser: Law, Matthew H, Aoude, Lauren G, Duffy, David L, Long, Georgina V, Johansson, Peter A, Pritchard, Antonia L, Khosrotehrani, Kiarash, Mann, Graham J, Montgomery, Grant W, Iles, Mark M, Cust, Anne E, Palmer, Jane M, Shannon, Kerwin F, Spillane, Andrew J, Stretch, Jonathan R, Thompson, John F, Saw, Robyn P M, Scolyer, Richard A, Martin, Nicholas G, Hayward, Nicholas K, MacGregor, Stuart
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container_end_page 2985
container_issue 17
container_start_page 2976
container_title Human molecular genetics
container_volume 29
creator Law, Matthew H
Aoude, Lauren G
Duffy, David L
Long, Georgina V
Johansson, Peter A
Pritchard, Antonia L
Khosrotehrani, Kiarash
Mann, Graham J
Montgomery, Grant W
Iles, Mark M
Cust, Anne E
Palmer, Jane M
Shannon, Kerwin F
Spillane, Andrew J
Stretch, Jonathan R
Thompson, John F
Saw, Robyn P M
Scolyer, Richard A
Martin, Nicholas G
Hayward, Nicholas K
MacGregor, Stuart
description Abstract Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological 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 are unknown. We hypothesize 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 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.
doi_str_mv 10.1093/hmg/ddaa156
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In addition to environmental etiological 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 are unknown. We hypothesize 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 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.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddaa156</identifier><identifier>PMID: 32716505</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Alleles ; Association Studies ; Cyclin-Dependent Kinase Inhibitor p16 - genetics ; Female ; Genetic Predisposition to Disease ; Germ-Line Mutation - genetics ; Humans ; Male ; Melanoma - epidemiology ; Melanoma - genetics ; Melanoma - pathology ; Melanoma, Cutaneous Malignant ; Multifactorial Inheritance - genetics ; Mutation - genetics ; Penetrance ; Skin Neoplasms - epidemiology ; Skin Neoplasms - genetics ; Skin Neoplasms - pathology ; Ultraviolet Rays - adverse effects</subject><ispartof>Human molecular genetics, 2020-10, Vol.29 (17), p.2976-2985</ispartof><rights>The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2020</rights><rights>The Author(s) 2020. Published by Oxford University Press. All rights reserved. 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In addition to environmental etiological 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 are unknown. We hypothesize 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 high-penetrance melanoma susceptibility genes. 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In addition to environmental etiological 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 are unknown. We hypothesize 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 high-penetrance melanoma susceptibility genes. 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source Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection
subjects Alleles
Association Studies
Cyclin-Dependent Kinase Inhibitor p16 - genetics
Female
Genetic Predisposition to Disease
Germ-Line Mutation - genetics
Humans
Male
Melanoma - epidemiology
Melanoma - genetics
Melanoma - pathology
Melanoma, Cutaneous Malignant
Multifactorial Inheritance - genetics
Mutation - genetics
Penetrance
Skin Neoplasms - epidemiology
Skin Neoplasms - genetics
Skin Neoplasms - pathology
Ultraviolet Rays - adverse effects
title Multiplex melanoma families are enriched for polygenic risk
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