CELL BIOLOGY AND MOLECULAR CARCINOGENESIS GROUP
AREAS OF EXPERTISE
Primary cell culture
Three-dimensional spheroid modeling of normal and cancer cells
shRNA, CRISPR/Cas9 gene knockdown
Lentiviral induced gene overexpression
Neoplastic phenotyping assays
Chemotherapeutic assays
CRISPR/Cas9 genome editing of genetic variants
CRISPR/Cas9 functional screens
Epigenome biology
LncRNA biology
Chromatin immunoprecipitation sequencing
RNA sequencing
SIMON GAYTHER, PHD
Professor and Director of Molecular Epidemiology
Dr. Gayther’s research program is largely focused on understanding the underlying causes of ovarian cancer initiation and development. Dr Gayther has a long established track record in defining the heritable component of ovarian cancer, and the functional role of both common and rare risk variants and their target susceptibility genes in the early stage disease pathogenesis.The overall approach of this research program is to integrate genomics and epigenomics analyses to identify molecular markers associated with disease, with cell biology modeling studies to validate the role of novel molecular markers in disease biology. The goal is to translate the findings from these studies into the clinical arena to improve risk prediction and prevention strategies, early stage screening and disease diagnosis and targeted therapeutics
PUBLICATIONS
Phelan C, Kuchenbaecker KB, Tyrer JP, Kar S, Lawrenson K, [...] Gayther SA. Genome wide association studies identify 12 novel susceptibility loci for different histological subtypes of epithelial ovarian cancer Nature Genetics 2016 (in press)
Kar SP, Beesley J, Amin Al Olama A [...] Gayther SA. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types. Cancer Discov. 2016 6:1052-67
Pharoah PD, Song H, Dicks E [...] Gayther SA. J. PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations. J Natl Cancer Inst. 2016 108(3)
Ramus SJ, Song H, Dicks E, Tyrer JP [...] Gayther SA. Mutations in the BRIP1, BARD1, PALB2and NBNgenes in women with ovarian cancer. J. Nat. Cancer Inst. 2015, 107(11)
Kelemen, LE, Lawrence K, Tyrer J, Li, Q [...] Gayther SA. Genome-wide significant risk associations for mucinous epithelial ovarian carcinoma. Nat. Genet. 2015, 47:888-97
Song H, Dicks E, Ramus SJ, Tyrer JP [...] Gayther SA. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J Clin Oncol. 2015, 33:2901-7
Kuchenbaecker KB, Ramus SJ, Tyrer J, Lee A [...] Gayther SA. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat Genet. 2015 47:164-71
Song H, Cicek MS, Dicks E, Harrington P, Ramus SJ, [...] Gayther SA. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 23:4703-9
Permuth-Wey J, Lawrenson K, Shen HC, Velkova A, Tyrer JP [...] Gayther SA. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31. Nat Commun. 2013 4:1627
Shen H, Fridley BL, Song H, Lawrenson K, Cunningham JM, [...] Gayther SA. Epigenetic Analysis Leads to Identification of HNF1B as a Subtype-Specific Susceptibility Gene for Ovarian Cancer. Nat Commun. 2013 4:1628
Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K [...] Gayther SA. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet. 2013 45:371-84
Pharoah PD, Tsai YY, Ramus SJ, Phelan CM, Goode [...] Gayther SA. GWAS meta-analysis and replication identifies three novel common susceptibility loci for ovarian cancer Nat Genet. 2013 45:362-70
Goode EL, Chenevix-Trench G, Song H, Ramus SJ, Notaridou M [...] Gayther SA. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 2010; 42:874-879
Bolton KL, Tyrer J, Song H, Ramus SJ, Notaridou M [...] Gayther SA. Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat Genet 2010; 42:880-884
Song H, Ramus SJ, Tyrer J, Bolton KL, Gentry-Maharaj A [...] Gayther SA. A genome-wide association study identifies a novel ovarian cancer susceptibility locus on 9p22.2. Nat Genet 2009; 41:996-1000
Soegaard M, Kjaer SK, Cox M, Wozniak E, Høgdall E, [...] Gayther SA. Contribution Of BRCA1 and BRCA2 Mutations and Clinical Characteristics in Ovarian Cancer Cases From Danish Population Clin Cancer Res 2008; 14:3761-3767
Ramus SJ, Harrington PA, Pye C, Dicioccio RA, Cox MJ, [...] Gayther SA. The contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Hum Mutation 2007; 28:1207-1215
Gayther SA, Batley S, Linger L, Bannister A, Thorpe K, et al. Mutations truncating the EP300 acetylase in human cancers. Nat. Genet. 2000, 43:851-857
Gayther SA, Russell P, Harrington P, Antoniou AC, Easton DF, Ponder BA. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. Am J Hum Genet 1999; 65:1021-1029
Gayther SA, Mangion J. Russell P, Seal S, Barfoot R, et al. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 1997,15:103-105
Foster KA, Harrington P, Kerr J, Russell P, DiCioccio RA, [...] Gayther SA. Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer. Cancer Res. 1996; 56:3622-3625
Gayther SA, Warren W, Mazoyer S, Russell PA, Harrington PA, et al. Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet 1995, 11:428-433
Candido Dos Reis FJ, Song H, Goode EL, Cunningham JM, Fridley BL, [...] Gayther SA. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer. Clin Cancer Res. 2015 21:652-657
Trabert B, Ness RB, Lo-Ciganic WH, Murphy MA, [...] Gayther SA. Aspirin, Nonaspirin Nonsteroidal Anti-inflammatory Drug, and Acetaminophen Use and Risk of Invasive Epithelial Ovarian Cancer: A Pooled Analysis in the Ovarian Cancer Association Consortium. J Natl Cancer Inst. 2014 106:djt431
Faber MT, Kjær SK, Dehlendorff C, Chang-Claude J, Andersen KK, [...] Gayther SA. Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies. Cancer Causes Control 2013 24:989-1004
Olsen CM, Nagle CM, Whiteman DC, Ness R, Pearce CL, [...] Gayther SA. Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium. Endocr Relat Cancer. 2013 20:251-262
Pearce CL, Templeman C, Rossing MA, Lee A, Near AM, [...] Gayther SA. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol. 2012 13:385-94
Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, Ramus SJ, [...] Gayther SA. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 2012, 307:382-90
Pharoah PD, Easton D, Stockton DL, Gayther SA, Ponder BA. Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group. Cancer Res 1999; 59:868-871
Kanska J, Zakhour M, Taylor-Harding B, Karlan BY, Wiedemeyer WR. Cyclin E as a potential therapeutic target in high grade serous ovarian cancer. Gynecologic Oncology. 2016 July 23.
Coetzee S, Shen H, Hazelett D, Lawrenson K, Li Q, [...] Gayther SA. Fine mapping and regulatory profiling of ovarian cancer susceptibility loci discovered by GWAS. Hum Mol Genet. 2015 24:3595-607
Adler EK, Mhawech-Fauceglia P, Gayther SA, Lawrenson, K. Evaluating the Expression of PAX8 in Ovarian Surface Epithelial Cells. Hum Pathol. 2015 46:948-56
Rodríguez-Malavé NI, Fernando TR, Patel PC, Contreras JR, Palanichamy JK, Tran TM, Anguiano J, Davoren MJ, Sandoval S, Crooks GM, and Rao DS. BALR-6 regulates cell growth and cell survival in B-lymphoblastic leukemia. Mol Can. 2015 14:1, 214
Fernando TR*, Rodríguez-Malavé NI*, Waters EV, Yan W, Casero D, Basso G, Pigazzi M, and Rao DS. LncRNA expression discriminates karyotype and regulates cell survival in B-lymphoblastic leukemia. Mol Can Res. 2015 13:5, 839-851. *Co-authorship
Köbel M, Madore J, Ramus SJ, Clarke BA, Pharoah PD, [...] Gayther SA. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study. Br J Cancer. 2014 111:2297-307
Köbel M, Kalloger SE, Lee S, Duggan MA, Kelemen LE, [...] Gayther SA. Biomarker-based ovarian carcinoma typing: a histologic investigation in the ovarian tumor tissue analysis consortium. Cancer Epidemiol Biomarkers Prev. 2013 22:1677-86
Sieh W, Köbel M, Longacre TA, Bowtell DD, deFazio A [...] Gayther SA. Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. Lancet Oncol. 2013, 14:853-62
Khalique L, Ayhan A, Jacobs IJ, Gayther SA, Ramus SJ. The clonal evolution of metastases from primary ovarian epithelial cancers. Int J Cancer 2009; 124:1579-1586
Høgdall EV, Christensen L, Kjaer SK, Blaakaer J, Jarle Christensen I, [...] Gayther SA. Protein expression levels of CarcinoEmbryonic Antigen (CEA) in Danish ovarian cancer patients. Pathology 2008; 40:487-492
Ramus SJ, Elmasry K, Luo Z, Gammerman A, Lu K, [...] Gayther SA. A Molecular Genetic Approach to improve the clinical diagnosis and clinical outcome of synchronous ovarian and endometrial cancer. Clin Cancer Res 2008; 14:5840-5848
Høgdall EV, Christensen L, Høgdall CK, Frederiksen K, Gayther S, et al. Distribution of p53 expression in tissue from 774 Danish ovarian tumour patients and its prognostic significance in ovarian carcinomas APMIS 2008; 116:400-409
Khalique L, Ayhan A, Weale ME, Jacobs IJ, Ramus SJ, Gayther SA. Genetic Intra Tumour Heterogeneity In Epithelial Ovarian Cancer: The Implications For Molecular Based Clinical Diagnosis Of Tumours J Pathol 2007; 211:286-295
Högdall EV, Christensen L, Högdall CK, Blaakaer J, Gayther SA, et al. Prognostic value of estrogen receptor and progesterone receptor tumor expression in Danish ovarian cancer patients: From the 'MALOVA' Ovarian Cancer Study. Oncol Rep 2007; 18:1051-1059
Høgdall EV, Christensen L, Kjaer SK, Blaakaer J, Christensen IJ, [...] Gayther SA. Expression level of Wilms tumor 1 (WT1) protein has limited prognostic value in epithelial ovarian cancer From the Danish "MALOVA" Ovarian Cancer Study. Gynecol Oncol 2007; 106:318-324
Högdall EV, Christensen L, Kjaer SK, Blaakaer J, Kjaerbye-Thygesen A, [...] Gayther SA. CA125 expression pattern, prognosis and correlation with serum CA125 in ovarian tumor patients. From The Danish " MALOVA" Ovarian Cancer Study. Gynaecologic Oncology 2007; 104:508-515
Brinkmann D, Ryan A. Ayhan A, McCluggage WG, Feakins R, Santibanez-Koref MF, Mein CA, Gayther SA, Jacobs IJ. A molecular genetic and statistical approach for the diagnosis of dual-site cancers. JNCI 2004; 96:1441-1446
Ramus SJ, Pharoah P. Harrington P, Pye C, Werness B, [...] Gayther SA. BRCA1/2 mutation status influences somatic genetic progression in inherited and sporadic epithelial ovarian cancer cases. Cancer Res 2003, 63:417-423
Russell PA, Pharoah PDP, De Foy K, Ramus SJ, Symmonds I, [...] Gayther SA. Frequent loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers. Int J Cancer 2000, 87:317-321
Manek R, Pakzamir E, Mhawech-Fauceglia P, Pejovic T, Sowter H, Gayther SA, Lawrenson K. Targeting Src in endometriosis-associated ovarian cancer. Oncogenesis. 2016 5:e251.
Lawrenson K, Lee N, Lee J, Rao N, Gayther SA. Src as a Novel Therapeutic Target for Ovarian Endometriosis. Gynecol Oncol. 2014 135:100-7
Lee J, Mhawech-Fauceglia P, Lee N, Parsanian JC, Lin YG, Gayther SA, Lawrenson K A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro. Lab Invest. 2013 93:528-42
Brueggmann, D, Templeman, C, Starzinski-Powitz, A, Rao, PN, Gayther, SA, Lawrenson, K. Novel Three dimensional in vitroModels of Ovarian Endometriosis. J Ovarian Res. 2014 7(1):17
Lawrenson K, Notaridou M, Lee N, Benjamin E, Jacobs IJ, [...] Gayther SA. In vitro three-dimensional modeling of fallopian tube secretory epithelial cells. BMC Cell Biol 2013, 14:43
Lawrenson K, Sproul D, Grun B, Notaridou M, Benjamin E, [...] Gayther SA. Modeling genetic and clinical heterogeneity in epithelial ovarian cancer. Carcinogenesis 2011, 32:2540-1549
Lawrenson K; Grun B; Benjamin E; Jacobs IJ; Dafou D; Gayther SA. Senescent Fibroblasts Promote Neoplastic Transformation of Ovarian Epithelial Cells in a Three-Dimensional Model of Early Stage Ovarian Cancer. Neoplasia 2010, 12:317-325
Lawrenson K; Benjamin E, Jacobs IJ, Gayther SA, Dafou D. In vitro Three-Dimensional Modeling of Human Ovarian Surface Epithelial Cells. Cell Proliferation 2009; 42:385-393
Grun B, Benjamin E, Sinclair J, Timms, J, Gayther SA, Dafou D. Three dimensional in vitro cell biology models of ovarian and endometrial cancer. Cell Proliferation 2009; 42:219-228
Li NF, Dafou D, Broad S, Lu YJ , Yang JS, Hagemann T, [...] Gayther SA. hTERT immortalised human ovarian surface epithelial cells maintain functional pRb and p53 expression. Cell Proliferation 2007, 40:780-794
Li NF, Willbanks G, Balkwill F, Jacobs IJ, Dafou D, Gayther SA. A Modified Culture Medium That Significantly Improves the Growth of Human Normal Ovarian Surface Epithelial (NOSE) Cells in Vitro. Lab Invest 2004; 84:923-931
Ross-Adams H, Ball S, Lawrenson K, Halim S, Russell R, [...] Gayther SA. HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer. Oncotarget. 2016 doi: 10.18632
Lawrenson, K, Siddhartha Kar, S, McCue, K, Kuchenbaeker, K [...] Gayther SA. Functional Mechanisms Underlying Pleiotropic Risk Alleles At The 19p13.1 Breast-Ovarian Cancer Susceptibility Locus. Nat. Comm. 2016 7:12675
Li, Q, Stram D, Haiman C, Kraft P, Pharoah PDP, Gayther SA, Karr S, Freedman MF. Expression QTL based analyses reveal candidate causal genes and loci across five tumor types. Hum Mol Genet. 2014 23:5294-302
Notaridou M, Quaye L, Dafou D, Jones C, Song H, [...] Gayther SA. Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer. Int J Cancer. 2011 128:2063-74
Spisak S, Lawrenson K, Fu Y, Csabai I, Cottman R, [...] Gayther SA. Establishing functional causality of non-coding GWAS variants using epigenome and genome editing. Nat. Med. 2015, 21:1357-6
Freedman ML, Monteiro, ANA, Gayther SA, Coetzee GA, et al. Principles for the post-GWAS functional characterization of cancer risk loci. Nat. Genet. 2011, 43:513-518
Lawrenson K, Li, Q, Kar S, Seo J-H [...] Gayther SA. Cis –eQTL Analysis And Functional Validation Of Candidate Susceptibility Genes For High-Grade Serous Ovarian Cancer. Nat. Comm. 2015, 6:8234