Combining common genetic variants and non-genetic risk factors to predict risk of cutaneous melanoma
File(s)ddy282.pdf (929.91 KB)
Accepted version
Author(s)
Type
Journal Article
Abstract
Melanoma heritability is among the highest for cancer and single nucleotide polymorphisms (SNPs) contribute to it. To date, only SNPs that reached statistical significance in genome-wide association studies or few candidate SNPs have been included in melanoma risk prediction models. We compared four approaches for building polygenic risk scores (PRS) using 12,874 melanoma cases and 23,203 controls from Melanoma Meta-Analysis Consortium as a training set, and newly genotyped 3,102 cases and 2,301 controls from the MelaNostrum consortium for validation. We estimated adjusted odds ratios (ORs) for melanoma risk using traditional melanoma risk factors and the PRS with the largest area under the Receiver Operator Characteristics curve (AUC). We estimated absolute risks combining the PRS and other risk factors, with age- and sex-specific melanoma incidence and competing mortality rates from Italy as an example. The best PRS, including 204 SNPs (AUC= 64.4%; 95% CI=63-65.8%), developed using winner's curse estimate corrections, had a per-quintile OR=1.35 (95% CI=1.30-1.41), corresponding to a 3.33-fold increase comparing the 5th to the 1st PRS quintile. The AUC improvement by adding the PRS was up to 7%, depending on adjusted factors and country. The 20-year absolute risk estimates based on the PRS, nevus count and pigmentation characteristics for a 60-year old Italian man ranged from 0.5% to 11.8% (RR=26.34), indicating good separation.
Date Issued
2018-12-01
Date Acceptance
2018-07-24
ISSN
0964-6906
Publisher
Oxford University Press (OUP)
Start Page
4145
End Page
4156
Journal / Book Title
Human Molecular Genetics
Volume
27
Issue
23
Copyright Statement
© 2018 Oxford University Press. This is a pre-copy-editing, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The definitive publisher-authenticated version Fangyi Gu, Ting-Huei Chen, Ruth M Pfeiffer, Maria Concetta Fargnoli, Donato Calista, Paola Ghiorzo, Ketty Peris, Susana Puig, Chiara Menin, Arcangela De Nicolo, Monica Rodolfo, Cristina Pellegrini, Lorenza Pastorino, Evangelos Evangelou, Tongwu Zhang, Xing Hua, Curt T DellaValle, D Timothy Bishop, Stuart MacGregor, Mark I Iles, Matthew H Law, Anne Cust, Kevin M Brown, Alexander J Stratigos, Eduardo Nagore, Stephen Chanock, Jianxin Shi, Melanoma Meta-Analysis Consortium, MelaNostrum Consortium, Maria Teresa Landi; Combining common genetic variants and non-genetic risk factors to predict risk of cutaneous melanoma, Human Molecular Genetics, , ddy282, is available online at: https://dx.doi.org/10.1093/hmg/ddy282
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30060076
5061268
Subjects
Adult
Aged
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Italy
Male
Melanoma
Middle Aged
Multifactorial Inheritance
Nevus
Polymorphism, Single Nucleotide
Risk Assessment
Risk Factors
Skin Neoplasms
Humans
Melanoma
Nevus
Skin Neoplasms
Genetic Predisposition to Disease
Risk Assessment
Risk Factors
Multifactorial Inheritance
Polymorphism, Single Nucleotide
Adult
Aged
Middle Aged
Italy
Female
Male
Genome-Wide Association Study
06 Biological Sciences
11 Medical and Health Sciences
Genetics & Heredity
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2018-08-31