Format

Send to

Choose Destination
See comment in PubMed Commons below
Br J Cancer. 2017 Feb 14;116(4):524-535. doi: 10.1038/bjc.2016.426. Epub 2017 Jan 19.

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

Author information

1
Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
2
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
3
Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
4
Bioinformatics and Computational Biology Research Center, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
5
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
6
Department of Epidemiology, Director of Genetic Epidemiology Research Institute, UCI Center for Cancer Genetics Research & Prevention, School of Medicine, University of California Irvine, Irvine, CA 92697, USA.
7
Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
8
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen Nuremberg, Universitaetsstrasse 21-23, Erlangen 91054, Germany.
9
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA.
10
Radiation Oncology Research Unit, Hannover Medical School, Hannover 30625, Germany.
11
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
12
Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki 00100, Finland.
13
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia.
14
Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia.
15
The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK.
16
German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg 69120, Germany.
17
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
18
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA.
19
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA 02215, USA.
20
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
21
Department of Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02-781, Poland.
22
Department of Epidemiology, The Geisel School of Medicine-at Dartmouth, Hanover, NH 03756, USA.
23
Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany.
24
Department of Gynecology, Jena-University Hospital-Friedrich Schiller University, Jena 07737, Germany.
25
Faculty of Medicine, University of Southampton, Southampton SO16 5YA, UK.
26
Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
27
Department of Surgery & Cancer, Imperial College London, London SW7 2AZ, UK.
28
Department of Women's Cancer, Institute for Women's Health, University College London, London W1T 7DN, UK.
29
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MI 55905, USA.
30
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
31
Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
32
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-001, Poland.
33
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft GmbH, Essen 45136, Germany.
34
Department of Gynecology and Gynecologic Oncology, Dr Horst Schmidt Kliniken Wiesbaden, Wiesbaden 65199, Germany.
35
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
36
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen 2100, Denmark.
37
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen 1165, Denmark.
38
The Juliane Marie Centre, Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark.
39
British Columbia's Ovarian Cancer Research (OVCARE) Program, Vancouver General Hospital, BC Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
40
Departments of Pathology and Laboratory Medicine and Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
41
Department of Molecular Oncology, BC Cancer Agency Research Centre, Vancouver, BC V5Z 1L3, Canada.
42
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
43
Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29435, USA.
44
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen 6500 HB, The Netherlands.
45
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark.
46
Vesalius Research Center, VIB, Leuven 3000, Belgium.
47
Laboratory for Translational Genetics, Department of Oncology, University of Leuven 3000, Belgium.
48
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
49
Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
50
Medical College of Xiamen University, Xiamen 361102, China.
51
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02-781, Poland.
52
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
53
Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Gynaecology, Nijmegen 6500 HB, The Netherlands.
54
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
55
Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow G12 0YN, UK.
56
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
57
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15213, USA.
58
Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
59
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612, USA.
60
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
61
The University of Texas School of Public Health, Houston, TX 77030, USA.
62
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki 00100, Finland.
63
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
64
Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR 97239, USA.
65
Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
66
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
67
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
68
Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
69
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06510, USA.
70
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
71
Department of Epidemiology, University of Washington, Seattle, WA 98109, USA.
72
Department of Gynecology and Obstetrics, Haukeland University Horpital, Bergen 5058, Norway.
73
Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen 5058, Norway.
74
Department of Community and Family Medicine, Duke University Medical Center, Durham, NC 27710, USA.
75
Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC 27710, USA.
76
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
77
Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC 3002, Australia.
78
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
79
Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center Medicine, Nashville, TN 37232, USA.
80
Department of Epidemiology, University of California Irvine, Irvine, CA 92697, USA.
81
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
82
The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.
83
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
84
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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<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.

PMID:
28103614
PMCID:
PMC5318969
[Available on 2018-02-14]
DOI:
10.1038/bjc.2016.426
[Indexed for MEDLINE]

MeSH terms, Supplementary concept, Grant support

MeSH terms

Supplementary concept

Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group
    Loading ...
    Support Center