Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)

Summary

Principal Investigator: Thomas A Sellers
Abstract: Deleterious mutations in BRCA1 and BRCA2 increase ovarian cancer risk substantially, but such mutations are rare in the population and collectively they account for fewer than 15 percent of cases. GWAS have successfully identified many common susceptibility alleles for multiple disease phenotypes, including the identification of genes involved in pathways not previously implicated in cancer. This has not been possible for ovarian cancer, but the recent/imminent completion of several independent GWAS with the potential for replication in participating OCAC studies provides the opportunity to achieve this and match the success for other cancers. In Project 1, the first aim is to pool data from four GWAS that used similar genotyping platforms, use several different approaches to analyze the data, and follow-up the most promising associations (SNPs and CNVs) in a large-scale replication in independent data sets. Genotypes are available from the lllumina HumanHap 610 chip on roughly 4400 cases and 4200 controls through UK and US GWAS, on 500 cases and 300 controls using the lllumina 317k chip, and a pooled DNA analysis of 520 cases and 900 controls in Australia which employed the lllumina 1M beadtype chip. In addition, the UK GWAS has genotyped nearly 22,000 promising SNPs on an additional roughly 5,000 cases and 5,000 controls;and the US GWAS will interrogate 16,000 SNPs on an additional 6,000 cases and 6,000 controls in October 2009. The second aim will be to replicate the findings using a custom iSelect lllumina chip of 13,680 beadtypes on a Stage III study population of an additional roughly 3,500 cases and 3,500 controls that have not been included in any of the previous Stage I or Stage II genotyping efforts. The total estimated three stage sample size will be approximately 16,400 cases and 17,100 controls, providing excellent power to detect risk alleles, critical to Projects 2 and 3. The third aim is to examine the association of SNPs and CNVs from all pooled Stage I and Stage II data in relation to ovarian cancer survival. For aim four we will design and run a custom iSelect lllumina chip of 3,072 SNPs on a Stage HI study population of additional cases for whom overall survival data are available. The total estimated three-stage survival sample size will be approximately 13,700 cases. We will fit ordinal genetic models to predict overall survival accounting for known clinical prognostic factors and conduct exploratory analysis of SNP associations within other major histologic subtypes (e.g., mucinous and clear cell).
Funding Period: 2010-07-02 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1
    Edwin S Iversen
    Department of Statistical Science, Duke University, Durham, North Carolina 27708, USA
    Cancer Epidemiol Biomarkers Prev 20:1078-88. 2011
  2. pmc Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31
    Jennifer Permuth-Wey
    Department of Cancer Epidemiology, Division of Population Sciences, Moffitt Cancer Center, Tampa, Florida, USA
    Nat Commun 4:1627. 2013
  3. pmc Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer
    Hui Shen
    USC Epigenome Center, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA
    Nat Commun 4:1628. 2013
  4. pmc GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer
    Paul D P Pharoah
    The Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
    Nat Genet 45:362-70, 370e1-2. 2013
  5. pmc In vitro three-dimensional modeling of fallopian tube secretory epithelial cells
    Kate Lawrenson
    Department of Preventive Medicine, University of Southern California Keck School of Medicine, 1450 Biggy Street, Los Angeles, California
    BMC Cell Biol 14:43. 2013
  6. pmc Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study
    Anja Rudolph
    Division of Cancer Epidemiology, German Cancer Research Center DKFZ, Im Neuenheimer Feld 581, D 69120 Heidelberg, Germany PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA Foundation for Quality and Efficiency in Health Care IQWIG, Cologne, Germany Human Genetics, Genome Institute of Singapore, Singapore, Singapore Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK INSERM National Institute of Health and Medical Research, CESP Center for Research in Epidemiology and Population Health, U1018, Environmental Epidemiology of Cancer, Villejuif, France Unité Mixte de Recherche Scientifique UMRS 1018, University Paris Sud, Villejuif, France Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr Universität Bochum IPA, Bochum, Germany Institute for Occupational Medicine and Maritime Medicine, University Medical Center, Hamburg Eppendorf, Hamburg, Germany Department of Internal Medicine, Telos Pharmaceuticals LLC
    Endocr Relat Cancer 20:875-87. 2013
  7. pmc Lessons from postgenome-wide association studies: functional analysis of cancer predisposition loci
    A N A Monteiro
    Cancer Epidemiology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
    J Intern Med 274:414-24. 2013
  8. pmc Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA
    Madalene A Earp
    Canada s Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
    Hum Genet 133:481-97. 2014
  9. pmc A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium
    Roger L Milne
    Human Cancer Genetics Programme and
    Hum Mol Genet 23:1934-46. 2014
  10. pmc Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions
    Anja Schoeps
    Department of Cancer Epidemiology, German Cancer Research Center DKFZ, Heidelberg, Germany Institute of Public Health, University of Heidelberg, Heidelberg, Germany
    Genet Epidemiol 38:84-93. 2014

Research Grants

  1. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
  2. Comparative Mechanisms of Cancer Chemoprevention
    Roderick H Dashwood; Fiscal Year: 2013

Detail Information

Publications26

  1. pmc A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1
    Edwin S Iversen
    Department of Statistical Science, Duke University, Durham, North Carolina 27708, USA
    Cancer Epidemiol Biomarkers Prev 20:1078-88. 2011
    ..In cases such as the breast and ovarian cancer syndrome in which prophylactic options can be severe and life changing, having information on the disease relevance of the VUS that a patient harbors can be critical...
  2. pmc Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31
    Jennifer Permuth-Wey
    Department of Cancer Epidemiology, Division of Population Sciences, Moffitt Cancer Center, Tampa, Florida, USA
    Nat Commun 4:1627. 2013
    ..An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes...
  3. pmc Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer
    Hui Shen
    USC Epigenome Center, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA
    Nat Commun 4:1628. 2013
    ..These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes...
  4. pmc GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer
    Paul D P Pharoah
    The Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
    Nat Genet 45:362-70, 370e1-2. 2013
    ..1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer...
  5. pmc In vitro three-dimensional modeling of fallopian tube secretory epithelial cells
    Kate Lawrenson
    Department of Preventive Medicine, University of Southern California Keck School of Medicine, 1450 Biggy Street, Los Angeles, California
    BMC Cell Biol 14:43. 2013
    ....
  6. pmc Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study
    Anja Rudolph
    Division of Cancer Epidemiology, German Cancer Research Center DKFZ, Im Neuenheimer Feld 581, D 69120 Heidelberg, Germany PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA Foundation for Quality and Efficiency in Health Care IQWIG, Cologne, Germany Human Genetics, Genome Institute of Singapore, Singapore, Singapore Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK INSERM National Institute of Health and Medical Research, CESP Center for Research in Epidemiology and Population Health, U1018, Environmental Epidemiology of Cancer, Villejuif, France Unité Mixte de Recherche Scientifique UMRS 1018, University Paris Sud, Villejuif, France Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr Universität Bochum IPA, Bochum, Germany Institute for Occupational Medicine and Maritime Medicine, University Medical Center, Hamburg Eppendorf, Hamburg, Germany Department of Internal Medicine, Telos Pharmaceuticals LLC
    Endocr Relat Cancer 20:875-87. 2013
    ..These findings warrant replication in independent studies...
  7. pmc Lessons from postgenome-wide association studies: functional analysis of cancer predisposition loci
    A N A Monteiro
    Cancer Epidemiology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
    J Intern Med 274:414-24. 2013
    ..Here, we outline strategies to functionally dissect predisposition loci and discuss their limitations as well as challenges for future studies. ..
  8. pmc Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA
    Madalene A Earp
    Canada s Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada
    Hum Genet 133:481-97. 2014
    ..84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes. ..
  9. pmc A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium
    Roger L Milne
    Human Cancer Genetics Programme and
    Hum Mol Genet 23:1934-46. 2014
    ..Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome...
  10. pmc Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions
    Anja Schoeps
    Department of Cancer Epidemiology, German Cancer Research Center DKFZ, Heidelberg, Germany Institute of Public Health, University of Heidelberg, Heidelberg, Germany
    Genet Epidemiol 38:84-93. 2014
    ..72-1.11, P for interaction = 3.2 × 10(-05)). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci...
  11. pmc Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10
    Bridget Charbonneau
    Authors Affiliations Departments of Health Sciences Research, Division of Epidemiology, Medical Oncology, Health Sciences Research, Division of Biomedical Statistics and Informatics, Immunology, and Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, Minnesota Department of Cancer Epidemiology, Division of Population Sciences, Moffitt Cancer Center, Tampa, Florida Channing Division of Network Medicine, Obstetrics and Gynecology Epidemiology Center, Brigham and Women s Hospital, Harvard Medical School Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut Department of Clinical Science, University of Bergen Departments of Gynecology and Obstetrics, and Pathology, Haukeland University Hospital, Bergen, Norway Departments for Health Evidence, Urology, and Gynaecology, Radboud University Medical Centre, Nijmegen Comprehensive Cancer Center The Netherlands, Utrecht, the Netherlands Cancer Epidemiology Centre, The Cancer Council Victoria Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, Department of Pathology, and Sir Peter MacCallum Department of Oncology, Austin and Repatriation Medical Centre
    Cancer Res 74:852-61. 2014
    ..Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted...
  12. pmc Integrative genomic analysis identifies epigenetic marks that mediate genetic risk for epithelial ovarian cancer
    Devin C Koestler
    Department of Biostatistics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
    BMC Med Genomics 7:8. 2014
    ..In the present study, we aimed to gain insight into this relationship by identifying DNA methylation marks that are candidate mediators of ovarian cancer genetic risk...
  13. pmc Analysis of over 10,000 Cases finds no association between previously reported candidate polymorphisms and ovarian cancer outcome
    Kristin L White
    Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
    Cancer Epidemiol Biomarkers Prev 22:987-92. 2013
    ....
  14. pmc Combined and interactive effects of environmental and GWAS-identified risk factors in ovarian cancer
    Celeste Leigh Pearce
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA
    Cancer Epidemiol Biomarkers Prev 22:880-90. 2013
    ..However, the interplay between such risk factors and susceptibility loci has not been studied...
  15. pmc Tandem BRCT Domains: DNA's Praetorian Guard
    Rafael D Mesquita
    Instituto Federal de Educação Ciência e Tecnologia, Rio de Janeiro, Brazil
    Genes Cancer 1:1140-6. 2010
    ..Here, we discuss emerging views of the origin and evolving roles of tandem BRCT domain repeats in the DNA damage response...
  16. pmc Yeast two-hybrid junk sequences contain selected linear motifs
    Yun Liu
    Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, 3400 N Charles St, Baltimore, Maryland, USA
    Nucleic Acids Res 39:e128. 2011
    ..0 on simulated data and apply the model to seven sets of experimentally derived OOF clones. Finally, we experimentally validate one SLiM found by our method, demonstrating its utility...
  17. pmc ENIGMA--evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes
    Amanda B Spurdle
    Queensland Institute of Medical Research, Brisbane, Australia
    Hum Mutat 33:2-7. 2012
    ..It is envisaged that the research and clinical application of models developed by ENIGMA will be relevant to the interpretation of sequence variants in other disease genes...
  18. pmc Common variation in Nemo-like kinase is associated with risk of ovarian cancer
    Kristen N Stevens
    Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA
    Cancer Epidemiol Biomarkers Prev 21:523-8. 2012
    ..Overexpression of mitotic kinases has been associated with prognosis, histologic grade, and clinical stage in ovarian cancer, but the relationship between inherited variation in these genes and ovarian cancer risk has not been well defined...
  19. pmc Ovarian cancer risk associated with inherited inflammation-related variants
    Kristin L White
    Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Cancer Res 72:1064-9. 2012
    ....
  20. pmc Gene set analysis of survival following ovarian cancer implicates macrolide binding and intracellular signaling genes
    Brooke L Fridley
    Departments of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA
    Cancer Epidemiol Biomarkers Prev 21:529-36. 2012
    ..Gene set analysis (GSA) overcomes this limitation by assessing overall evidence for association of a phenotype with all measured variation in a set of genes...
  21. pmc BRCT domains: A little more than kin, and less than kind
    Dietlind L Gerloff
    Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064, USA
    FEBS Lett 586:2711-6. 2012
    ..Here we discuss the biology of BRCT domains and how a domain-centric analysis can aid in the understanding of signal transduction events in the DNA damage response network...
  22. pmc Inherited variants in regulatory T cell genes and outcome of ovarian cancer
    Ellen L Goode
    Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America
    PLoS ONE 8:e53903. 2013
    ..1×10(-4)) among all cases combined. As the products of these genes are known to affect induction, trafficking, or immunosuppressive function of Tregs, these results suggest the need for follow-up phenotypic studies...
  23. ncbi A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro
    Janet Myungjin Lee
    Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
    Lab Invest 93:528-42. 2013
    ..These findings could also impact in vitro modeling approaches and drug development strategies for other solid tumor types...

Research Grants31

  1. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  2. Comparative Mechanisms of Cancer Chemoprevention
    Roderick H Dashwood; Fiscal Year: 2013
    ..This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet. ..