Sharon Johnatty

• PhD
• QIMR Berghofer Medical Research Institute

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status...

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status...

Background: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC. Methods: We performed a retrospective cohort analysis of pa...

Objective: Studies on low-grade serous ovarian cancer (LGSC) are limited by a low number of cases. The aim of this study was to define the prognostic significance of age, stage, and CA-125 levels on survival in a multi-institutional cohort of women with pathologically confirmed LGSC. Methods: Women with LGSC were identified from the collaborativ...

Hereditary endometrial cancer (EC) is most commonly attributed to pathogenic variants in mismatch repair (MMR) genes. Evidence supports existence of additional genetic risk factors in the context of multiple cancer diagnoses and/or family history of EC. EC patients (n=5292) referred for diagnostic multi-gene cancer panel testing were annotated for:...

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of P...

Purpose Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between...

Objective Medical research studies often rely on the manual collection of data from scanned typewritten clinical records, which can be laborious, time consuming and error prone because of the need to review individual clinical records. We aimed to use text mining to assist with the extraction of clinical features from complex text-based scanned pat...

Background Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is approximately four years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for overall survival in HGSO...

Leiomyomas, adenomyosis, and endometriosis are reported to be risk factors for endometrial carcinoma (EC), and adenomyosis and endometriosis also for ovarian carcinoma (OC). We aimed to describe the prevalence of these conditions in EC patients with or without an OC diagnosis, and to investigate their relationship with EC risk and prognostic factor...

We hypothesized that endometrial carcinoma (EC) patients with a prior cancer diagnosis, after accounting for EC arising after tamoxifen‐treated prior breast carcinoma, are more likely to have an underlying genetic basis. We used information from a population‐based study to compare measured risk factors, tumor characteristics, survival, and known mi...

Objective: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. Patients and methods: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival a...

Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequate...

Importance Cytotoxic CD8⁺ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8⁺ TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8⁺ TILs in epithelial ovarian cancer. Design, Setting, and...

Objective: To determine endometrial cancer (EC) risk according to family cancer history, including assessment by degree of relatedness, type of and age at cancer diagnosis of relatives. Methods: Self-reported family cancer history was available for 1353 EC patients and 628 controls. Logistic regression was used to quantify the association betwee...

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants a...

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants a...

The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray geno...

Objective: To investigate the association between breastfeeding and endometrial cancer risk using pooled data from 17 studies participating in the Epidemiology of Endometrial Cancer Consortium. Methods: We conducted a meta-analysis with individual-level data from three cohort and 14 case-control studies. Study-specific odds ratios (ORs) and 95%...

Purpose: Cancer antigen 125 (CA125) is a glycoprotein expressed by epithelial cells of several normal tissue types and overexpressed by several epithelial cancers. Serum CA125 levels are mostly used as an aid in the diagnosis of ovarian cancer patients, to monitor response to treatment and detect cancer recurrence. Besides tumor characteristics, C...

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11...

Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immune suppressive/pro-tumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be one prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian...

Objective: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore,...

OBJECTIVE: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, w...

OBJECTIVE: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, w...

Background: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene–environment interactions related to hormone-related risk factors could differ between obese and non-obese women. Methods: We considered intera...

Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase geno...

Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-ba...

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Germline genetic variation can affect chemotherapeutic drug disposition, toxicity and efficacy. Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize individual treatment. Compared to the traditional candida...

Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI...

Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. We analyzed ~2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian c...

Background: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 e...

Primary and acquired chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that heritable polymorphisms might be associated with clinical outcome. Through the Ovarian Cancer Association Consortium, we have collected detailed clinical data from a large number of ovarian cancer patients. We have conducte...

Background ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. Methods The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was...

ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with o...

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer....

The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R,...

Introduction: Epithelial ovarian cancer is generally treated by cytoreductive surgery followed by paclitaxel and carboplatin combination chemotherapy. Despite the high initial response rate, most patients with advanced disease will relapse and eventually succumb to illness due to intrinsic or acquired chemotherapy resistance. ABCB1 (ATP–binding cas...

Objective: ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC). Methods: The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236...

Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. 12 studies participat...

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also...

TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measur...

Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. METHODS: Twenty-seve...

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed approximately 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measureme...

Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some o...

Cell-based models have shown that response to chemotherapy has a heritable component. We hypothesized that in order to identify loci associated with treatment outcome we should focus on cases known to have had uniform chemotherapy for epithelial ovarian cancer. We therefore performed a two-stage genome-wide association study (GWAS) of progression f...

Genome-wide association studies have implicated the TERT-CLPTM1L locus at 5p15.33 in susceptibility to a variety of cancers including pancreas, lung, skin and glioma, suggesting that TERT may act as a “pan-cancer susceptibility locus” in a similar manner to the 8q24 region. We initially identified an association between an intronic TERT SNP rs7726...

Background / Purpose: Several independent genome-wide association studies have implicated polymorphisms in the TERT-CLPTM1L locus at 5p15.33 in cancer risk. Fine-mapping of this region has identified single nucleotide polymorphisms (SNPs) in the upstream promoter region of TERT, which encodes the reverse transcriptase subunit of telomerase. The m...

Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. To characterize the survival of BRCA carriers with EOC compared with noncarriers and to...

The association of rs2736109/rs2736108 with risk of invasive breast cancer, by study (DOC)

Per allele OR for all SNPs in EOC (DOC)

Participating invasive breast case-control studies (DOC)

Participating EOC case-control studies (DOC)

The association of rs2736109 with EOC, by study (DOC)

Breast cancer risk by ER status (DOC)

Breast cancer risk by age (DOC)

Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at...

Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at...

Invasive ovarian cancer is a significant cause of gynecologic cancer mortality. We examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used...

Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMa...

Sensitivity analysis for DCN rs516115 and serous epithelial ovarian cancer stratified by case recruitment period. Forest plots represent associations represent ORs (95% CI) for individual study (squares) and study-adjusted pooled (diamonds) estimates. Models are ordinal genetic risk models. HAN-HJO and HAN-HMO were combined for presentation. Phet r...

Sensitivity analysis for LUM rs17018765 and serous epithelial ovarian cancer stratified by case recruitment period. Forest plots represent associations represent ORs (95% CI) for individual study (squares) and study-adjusted pooled (diamonds) estimates. Models are ordinal genetic risk models. HAN-HJO and HAN-HMO were combined for presentation. Phet...

Genotype counts, MAF and HWE statistics and associations between genotypes and risk of ovarian carcinoma for DCN and LUM SNPs among Caucasian subjects in OCAC replication set 2. (DOC)

Haplotype analysis of decorin and lumican genes and invasive serous epithelial ovarian cancer risk among 1,317 Caucasian subjects in the discovery set. (DOC)

Overview of 18 OCAC studies with serous epithelial ovarian cancer cases and controls. (DOC)

Ethics statement. (DOC)

Linkage disequilibrium blocks for tagSNPs in DCN and LUM. Analysis is based on total number of controls from the discovery set and replication set 1. The two genes comprise a contiguous segment on chromosome 12 of approximately 80 kb. Numbers in the squares on the LD block indicate the correlation (r2) between SNPs. * indicates SNPs that were signi...

SNP and location, HWE test P-value and MAF for variants in DCN and LUM in 920 controls in the discovery set and 1,098 controls in replication set 1. (DOC)

Sensitivity analysis for DCN rs13312816 and serous epithelial ovarian cancer stratified by case recruitment period. Forest plots represent associations represent ORs (95% CI) for individual study (squares) and study-adjusted pooled (diamonds) estimates. Models are ordinal genetic risk models. HAN-HJO and HAN-HMO were combined for presentation. Phet...

Odds ratios (OR) and 95% confidence intervals (CI) for the association between genetic polymorphisms in DCN and LUM and serous epithelial ovarian cancer risk among 1,317 Caucasian subjects in the discovery set. (DOC)

Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) am...

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL We performed a multi-stage genome-wide association study (GWAS) for drug response in ovarian cancer. We selected 313 chemotherapy treated patients from the Australian Ovarian Cancer Study (AOCS). Patients were treated with paclitaxel/carboplatin and the trait of interest was...

An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3'-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. Ho...

ABCC11 is an ATP-binding cassette transporter responsible for the transport of a diverse range of lipophilic compounds. A single nucleotide polymorphism (SNP) encoding an amino acid change has recently been shown to determine whether cerumen (earwax) is wet or dry. We hypothesised that this ABCC11 SNP may be associated with breast cancer risk becau...

Identifying patients prior to treatment that are less likely to benefit from or most likely to experience adverse events from chemotherapeutic agents is essential. Even though humans are the most relevant system, pharmacogenomic discovery in the field of oncology is plagued by difficulties in executing large clinical trials and confounding factors...

Introduction: Alterations in components of the stromal tissue that underlie the epithelium can initiate, promote or inhibit epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) are stromal genes with reduced expression in serous ovarian cancer. We hypothesized that single nucleotide polymorphisms (SNPs) in these genes may influence susceptibil...

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis...

Candidate genes, putative role/special justification for selection and reference list. (0.05 MB DOC)

Characteristics of serous ovarian cancer cases and controls used in discovery and replication analyses according to contributing OCAC study. (0.05 MB DOC)

SNPs successfully genotyped (Illumina & Sequenom) in the discovery stage with PTrend≤0.05 for serous ovarian cancer risk. (0.12 MB DOC)

Study design for two-stage analysis of selected SNPs in genes involved in stromal-epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). (0.08 MB TIF)

Study heterogeneity p-values for serous ovarian cancer risk estimates among non-Hispanic whites for SNPs reported in Table 2. (0.04 MB DOC)

Candidate gene selection and justification. (0.06 MB DOC)