|
|
|
|
|
|
|
|
Abstract
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.
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 (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<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 × 10−8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=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.
0 comments :
Post a Comment
Your comments?
Note: Only a member of this blog may post a comment.