Combined analysis of keratinocyte cancers identifies novel genome-wide loci.
Alleles
Carcinoma, Basal Cell
/ genetics
Carcinoma, Squamous Cell
/ genetics
Case-Control Studies
Computational Biology
/ methods
Gene Expression Profiling
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Keratinocytes
/ metabolism
Molecular Sequence Annotation
Odds Ratio
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Quantitative Trait, Heritable
Skin Neoplasms
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
15 09 2019
15 09 2019
Historique:
received:
14
03
2019
revised:
30
05
2019
accepted:
03
06
2019
pubmed:
8
6
2019
medline:
10
3
2020
entrez:
8
6
2019
Statut:
ppublish
Résumé
The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5-1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.
Identifiants
pubmed: 31174203
pii: 5512167
doi: 10.1093/hmg/ddz121
pmc: PMC6737293
doi:
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3148-3160Informations de copyright
© The Author(s) 2019. Published by Oxford University Press.
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