Combined analysis of keratinocyte cancers identifies novel genome-wide loci.

Combined analysis of keratinocyte cancers identifies novel genome-wide loci.

Publication date: Jun 07, 2019

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.

Liyanage, U.E., Law, M.H., Han, X., An, J., Ong, J.S., Gharahkhani, P., Gordon, S., Neale, R.E., Olsen, C.M., MacGregor, S., and Whiteman, D.C. Combined analysis of keratinocyte cancers identifies novel genome-wide loci. 22892. 2019 Hum Mol Genet.

Concepts Keywords
Australia Healthcare
Basal Keratinocyte cancers
BRCA2 Immunotherapy
Carcinoma Branches of biology
CTLA4 Statistical genetics
Europe Genetic architecture
Gene Genetic correlation
Genetic Gwas
Genome Genetics of tuberculosis
Healthcare GWAS in allergy
High Penetrance
Immunotherapy
Keratinocyte
Linkage Disequilibrium
Loci
Melanoma
Regression
Squamous Carcinoma

Semantics

Type Source Name
pathway BSID Basal cell carcinoma
disease DOID basal cell carcinoma
disease MESH basal cell carcinoma
disease MESH cancers
pathway BSID Melanoma
disease MESH melanoma
disease DOID melanoma
gene UNIPROT CTLA4
gene UNIPROT BRCA2
gene UNIPROT SET
gene UNIPROT SGSM3
disease MESH multiple
disease DOID cancer
gene UNIPROT SERPINB3
disease DOID squamous cell carcinoma
disease MESH squamous cell carcinoma

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