Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci.

Br J Cancer
Authors
Siddhartha Kar
Emily Adler
Jonathan Tyrer
Dennis Hazelett
Hoda Anton-Culver
Elisa Bandera
Matthias Beckmann
Andrew Berchuck
Natalia Bogdanova
Louise Brinton
Ralf Butzow
Ian Campbell
Karen Carty
Jenny Chang-Claude
Linda Cook
Daniel Cramer
Julie Cunningham
Agnieszka Dansonka-Mieszkowska
Jennifer Doherty
Thilo Dörk
Matthias Dürst
Diana Eccles
Peter Fasching
James Flanagan
Aleksandra Gentry-Maharaj
Rosalind Glasspool
Ellen Goode
Marc Goodman
Jacek Gronwald
Florian Heitz
Michelle Hildebrandt
Estrid Høgdall
Claus Høgdall
David Huntsman
Allan Jensen
Beth Karlan
Linda Kelemen
Lambertus Kiemeney
Susanne Kjaer
Jolanta Kupryjanczyk
Diether Lambrechts
Douglas Levine
Qiyuan Li
Jolanta Lissowska
Karen Lu
Jan Lubinski
Leon Massuger
Valerie McGuire
Iain McNeish
Usha Menon
Francesmary Modugno
Alvaro Monteiro
Kirsten Moysich
Roberta Ness
Heli Nevanlinna
James Paul
Celeste Pearce
Tanja Pejovic
Jennifer Permuth
Catherine Phelan
Malcolm Pike
Elizabeth Poole
Susan Ramus
Harvey Risch
Mary Rossing
Helga Salvesen
Joellen Schildkraut
Thomas Sellers
Mark Sherman
Nadeem Siddiqui
Weiva Sieh
Honglin Song
Melissa Southey
Kathryn Terry
Shelley Tworoger
Christine Walsh
Nicolas Wentzensen
Alice Whittemore
Anna Wu
Hannah Yang
Wei Zheng
Argyrios Ziogas
Matthew Freedman
Simon Gayther
Paul Pharoah
Kate Lawrenson
Abstract

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

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.
Year of Publication
2017
Journal
Br J Cancer
Volume
116
Issue
4
Pages
524-535
Date Published
2017 Feb 14
ISSN
1532-1827
DOI
10.1038/bjc.2016.426
PubMed ID
28103614
PubMed Central ID
PMC5318969
Links
Grant list
U01 CA069417 / CA / NCI NIH HHS / United States
R01 CA050385 / CA / NCI NIH HHS / United States
G0501974 / Medical Research Council / United Kingdom
N01 PC067010 / PC / NCI NIH HHS / United States
P50 CA159981 / CA / NCI NIH HHS / United States
P30 CA016056 / CA / NCI NIH HHS / United States
R01 CA087538 / CA / NCI NIH HHS / United States
R01 CA136924 / CA / NCI NIH HHS / United States
P01 CA087969 / CA / NCI NIH HHS / United States
R01 CA067262 / CA / NCI NIH HHS / United States
R01 CA106414 / CA / NCI NIH HHS / United States
M01 RR000056 / RR / NCRR NIH HHS / United States
R01 CA095023 / CA / NCI NIH HHS / United States
UM1 CA176726 / CA / NCI NIH HHS / United States
R37 CA070867 / CA / NCI NIH HHS / United States
R03 CA113148 / CA / NCI NIH HHS / United States
R01 CA058598 / CA / NCI NIH HHS / United States
K22 CA138563 / CA / NCI NIH HHS / United States
R01 CA058860 / CA / NCI NIH HHS / United States
R01 CA080742 / CA / NCI NIH HHS / United States
R01 CA074850 / CA / NCI NIH HHS / United States
R01 CA063678 / CA / NCI NIH HHS / United States
N01PC35137 / CA / NCI NIH HHS / United States
K07 CA092044 / CA / NCI NIH HHS / United States
R00 CA184415 / CA / NCI NIH HHS / United States
P50 CA105009 / CA / NCI NIH HHS / United States
K07 CA080668 / CA / NCI NIH HHS / United States
R01 CA064277 / CA / NCI NIH HHS / United States
P30 CA014089 / CA / NCI NIH HHS / United States
R01 CA083918 / CA / NCI NIH HHS / United States
R03 CA115195 / CA / NCI NIH HHS / United States
UM1 CA186107 / CA / NCI NIH HHS / United States
R01 CA054419 / CA / NCI NIH HHS / United States
R01 CA122443 / CA / NCI NIH HHS / United States
P30 CA015083 / CA / NCI NIH HHS / United States
R01 CA076016 / CA / NCI NIH HHS / United States
K07 CA143047 / CA / NCI NIH HHS / United States
R01 CA087696 / CA / NCI NIH HHS / United States
U19 CA148112 / CA / NCI NIH HHS / United States
R01 CA149429 / CA / NCI NIH HHS / United States
P01 CA017054 / CA / NCI NIH HHS / United States
N01 CN025403 / CA / NCI NIH HHS / United States
R01 CA049449 / CA / NCI NIH HHS / United States
R01 CA063682 / CA / NCI NIH HHS / United States
UM1 CA182910 / CA / NCI NIH HHS / United States
K07 CA095666 / CA / NCI NIH HHS / United States
R01 CA112523 / CA / NCI NIH HHS / United States
P50 CA136393 / CA / NCI NIH HHS / United States
R01 CA126841 / CA / NCI NIH HHS / United States
R01 CA114343 / CA / NCI NIH HHS / United States

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