Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci
PBN-AR
Instytucja
Centrum Onkologii - Instytut im. Marii Skłodowskiej-Curie
Informacje podstawowe
Główny język publikacji
English
Czasopismo
British Journal of Cancer (40pkt w roku publikacji)
ISSN
0007-0920
EISSN
1532-1827
Wydawca
Springer Nature
DOI
URL
Rok publikacji
2017
Numer zeszytu
4
Strony od-do
524-535
Numer tomu
116
Identyfikator DOI
Liczba arkuszy
0.55
Autorzy
Pozostali autorzy
+ 83
Streszczenia
Język
en
Treść
Background: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. Methods: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). Results: The PAX8-target gene set was ranked 1/615 in the discovery (P-GSEA<0.001; FDR = 0.21), 7/615 in the replication (P-GSEA = 0.004; FDR = 0.37), and 1/615 in the combined (P-GSEA<0.001; FDR = 0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P = 0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10(-5) (including six with P<5 x 10(-8)). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (P-GSEA = 0.025) and IGROV1 (P-GSEA = 0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. Conclusions: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.
Inne
System-identifier
COI19c43a565bf249c8a968d0811b2ff4e3
CrossrefMetadata from Crossref logo
Cytowania
Liczba prac cytujących tę pracę
Brak danych
Referencje
Liczba prac cytowanych przez tę pracę
Brak danych