ORCID Profile
0000-0003-1017-0372
Current Organisations
Sydney Children's Hospital
,
Children's Cancer Institute Australia
,
University of New South Wales
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Publisher: Springer Science and Business Media LLC
Date: 24-01-2018
DOI: 10.1007/S10689-018-0071-9
Abstract: Assessing adherence behavior among mutation carriers to cancer risk management guidelines is important for both service improvement and cost-effectiveness analyses, but such real-world data is often lacking. The present study aims to report adherence rates among mutation carriers in a recently established cancer genetics program in Singapore. We conducted a medical chart review of mutation carriers who had attended for genetic counseling and gathered data regarding risk management behavior, including cancer surveillance and/or risk-reducing surgery, and cancers subsequently detected. Of the 52 subjects included in the study, the majority were affected prior to genetic testing (78.8%) and had family history suggestive of a germline mutation (88.5%). The overall adherence rate was 96.2%, including 37 (74.0%) fully-adherent and 13 (26.0%) partially-adherent subjects, with five cancers subsequently detected. Among the 28 BRCA1/2 mutation carriers, adherence to breast cancer risk management was also high (89.3%), although uptake of risk-reducing bilateral salpingo-oophorectomy was not as common (60%). Whilst overall adherence in this cohort was high, BRCA1/2 mutation carriers may require targeted interventions to improve ovarian cancer risk management uptake. Additionally, further education among health professionals and the wider community regarding cancer genetics is needed to ensure the early identification of mutation carriers.
Publisher: Oxford University Press (OUP)
Date: 10-2018
Abstract: Growing evidence suggests a role for cancer susceptibility genes such as BRCA2 and PALB2 in young-onset colorectal cancers. Using a cohort of young colorectal cancer patients, we sought to identify and provide functional evidence for germline pathogenic variants of DNA repair genes not typically associated with colorectal cancer. We recruited 88 patients with young-onset colorectal cancers seen at a general oncology center. Whole-exome sequencing was performed to identify variants in DNA repair and colorectal cancer predisposition genes. Pathogenic BRCA2 and PALB2 variants were analyzed using immunoblot and immunofluorescence on patient-derived lymphoblastoid cells. In general, our cohort displayed characteristic features of young-onset colorectal cancers. Most patients had left-sided tumors and were diagnosed at late stages. Four patients had familial adenomatous polyposis, as well as pathogenic APC variants. We identified 12 pathogenic variants evenly distributed between DNA repair and colorectal cancer predisposition genes. Six patients had pathogenic variants in colorectal cancer genes: APC (n = 4) and MUTYH monoallelic (n = 2). Another six had pathogenic variants in DNA repair genes: ATM (n = 1), BRCA2 (n = 1), PALB2 (n = 1), NTHL1 (n = 1), and WRN (n = 2). Pathogenic variants BRCA2 c.9154C T and PALB2 c.1059delA showed deficient homologous recombination repair, evident from the impaired RAD51 nuclear localization and foci formation. A substantial portion of pathogenic variants in young-onset colorectal cancer was found in DNA repair genes not previously associated with colorectal cancer. This may have implications for the management of patients. Further studies are needed to ascertain the enrichment of pathogenic DNA repair gene variants in colorectal cancers.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.JNEUMETH.2010.08.018
Abstract: Changes in gene expression and splicing patterns (that occur prior to the onset and during the progression of complex diseases) have become a major focus of neurodegenerative disease research. These signature patterns of gene expression provide clues about the mechanisms involved in the molecular pathogenesis of neurodegenerative disease and may facilitate the discovery of novel therapeutic drugs. With the development of array technologies and the very recent RNA-seq technique, our understanding of the pathogenesis of neurodegenerative disease is expanding exponentially. Here, we review the technologies involved in gene expression and splicing analysis and the related literature on three common neurodegenerative diseases: Alzheimer's disease, Parkinson's disease and Huntington's disease.
Publisher: American Chemical Society (ACS)
Date: 23-01-2020
Publisher: Springer Science and Business Media LLC
Date: 13-09-2019
DOI: 10.1038/S41525-019-0096-5
Abstract: Cascade testing for cancer predisposition offers a highly efficient and cost-effective method for identifying in iduals at increased risk for cancer, in whom targeted interventions can often improve survival. The aim of this study was to determine the impact of free cascade testing on uptake and identify other associated factors. Demographic and clinical data were gathered prospectively for 183 probands found to have a pathogenic variant associated with cancer predisposition and their 826 first-degree relatives (FDRs). The provision of free cascade testing was significantly associated with uptake (21.6% vs 6.1% χ 2 , P 0.001). Relationship type between FDR and proband and FDR age also demonstrated significant associations, suggesting greater engagement amongst younger generations. Overall, 29.0% (53/183) of families had at least 1 FDR who underwent cascade testing. Of these families, 67.9% (36/53) had an uptake rate of at least 40.0%. Cost is a significant barrier to cascade testing uptake in Singapore. Tailored interventions targeting underrepresented groups and genetic counseling approaches supporting family communication and decision-making are necessary.
Publisher: Wiley
Date: 20-07-2017
DOI: 10.1002/MGG3.313
Publisher: Cold Spring Harbor Laboratory
Date: 08-2019
DOI: 10.1101/MCS.A004093
Abstract: Germline pathogenic variants in BRCA1/2 account for one-third of familial breast cancers. The majority of BRCA1 function requires heterodimerization with BARD1. In contrast to BRCA1 , BARD1 is a low-penetrance gene with an unclear clinical relevance, partly because of limited functional evidence. Using patient-derived lymphoblastoid cells, we functionally characterized two pathogenic variants (c.1833dupT, c.2099delG) and three variants of uncertain significance (VUSs) (c.73G C, c.1217G A, c.1918C A). Three of these patients had breast cancers, whereas the remaining had colorectal cancers ( n = 3). Both patients with pathogenic variants (c.1833dupT, c.2099delG) developed breast cancers with aggressive disease phenotypes such as triple-negative breast cancer and high cancer grades. As BARD1 encompasses multiple functional domains, including those of apoptosis and homologous recombination repair, we hypothesized that the function being impaired would correspond with the domain where the variant was located. Variants c.1918C A, c.1833dupT, c.1217G A, and c.2099delG, located within and proximal to apoptotic domains of ankyrin and BRCT, were associated with impaired apoptosis. Conversely, apoptosis function was preserved in c.73G C, which was distant from the ankyrin domain. All variants displayed normal BRCA1 heterodimerization and RAD51 colocalization, consistent with their location being distal to BRCA1—and RAD51-binding domains. In view of deficient apoptosis, VUSs (c.1217G A and c.1918C A) may be pathogenic or likely pathogenic variants. In summary, functional analysis of BARD1 VUSs requires a combination of assays and, more importantly, the use of appropriate functional assays with consideration to the variant's location.
Publisher: Springer Science and Business Media LLC
Date: 12-11-2018
DOI: 10.1038/S41439-018-0031-9
Abstract: Pallister-Hall syndrome is a rare autosomal dominant condition that is associated with polydactyly and hypothalamic hamartoma and is caused predominantly by frameshift or nonsense pathogenic variants in the GLI3 gene. The majority of cases are identified during childhood however, rare reports of diagnoses during adulthood exist. Here, we describe the identification of a novel nonsense GLI3 pathogenic variant in an adult male following the incidental detection of a hypothalamic hamartoma.
Publisher: Wiley
Date: 24-05-2018
DOI: 10.1007/S10897-018-0259-Z
Abstract: The increase in demand for clinical cancer genetics services has impacted the ability to provide services timeously. Given limited resources, this often results in extended appointment waiting times. Over the last 3 years, the Cancer Genetics Service at the National Cancer Centre Singapore has continued to experience a steady increase in demand for its service. Nevertheless, significant no-show rates have been reported. This study sought to determine whether an association exists between appointment waiting times and attendance rates. Data was gathered for all participants meeting inclusion criteria. Attendance rates and appointment waiting times were calculated. The relationship between mean waiting times for those who did and did not attend their scheduled appointments was evaluated using Welch's t test and linear regression model. The results showed a significant difference in mean appointment waiting times between patients who did and did not attend (32.66 versus 43.50 days respectively p < 0.0001). Furthermore, patients who waited for longer than 37 days were significantly less likely to attend. No-show rates increased as the waiting time increased, at a rate of 19.60% per 20 days and 21.40% per 30 days. In conclusion, appointment waiting time is a significant predictor for patient attendance. Strategies to ensure patients receive an appointment within the necessary timeframe at the desired setting are important to ensure that in iduals at increased cancer risk attend their appointments in order to manage their cancer risks effectively.
Publisher: MDPI AG
Date: 14-11-2022
Abstract: A high salt (HS) diet is associated with an increased risk for cardiovascular diseases (CVDs) and fibrosis is a key contributor to the organ dysfunction involved in CVDs. The activation of the renin angiotensin type 2 receptor (AT2R) has been considered as organ protective in many CVDs. However, there are limited AT2R-selective agonists available. Our first reported β-substituted angiotensin III peptide, β-Pro7-AngIII, showed high selectivity for the AT2R. In the current study, we examine the potential anti-fibrotic and anti-inflammatory effects of this novel AT2R-selective peptide on HS-induced organ damage. FVB/N mice fed with a 5% HS diet for 8 weeks developed cardiac and renal fibrosis and inflammation, which were associated with increased TGF-β1 levels in heart, kidney and plasma. Four weeks’ treatment (from weeks 5–8) with β-Pro7-AngIII inhibited the HS-induced cardiac and renal fibrosis and inflammation. These protective effects were accompanied by reduced local and systemic TGF-β1 as well as reduced cardiac myofibroblast differentiation. Importantly, the anti-fibrotic and anti-inflammatory effects caused by β-Pro7-AngIII were attenuated by the AT2R antagonist PD123319. These results demonstrate, for the first time, the cardio- and reno-protective roles of the AT2R-selective β-Pro7-AngIII, highlighting it as an important therapeutic that can target the AT2R to treat end-organ damage.
Publisher: Springer Science and Business Media LLC
Date: 13-05-2020
Publisher: Wiley
Date: 16-10-2018
DOI: 10.1002/PON.4902
Abstract: Malays comprise an Asian cultural group reported to have low breast cancer screening uptake rates and poor cancer outcomes. Little is known about Malay cultural factors influencing beliefs and practice of cancer screening and genetic testing. Our study aims to explore health beliefs of Malay women around breast cancer screening and genetic testing. We conducted focus groups among healthy English-speaking Malay women in Singapore, aged 40 to 69 years, using a structured guide developed through literature review, expertise input and participant refinement. Thematic analysis was conducted to extract dominant themes representing key motivators and barriers to screening and genetic testing. We used grounded theory to interpret results and derive a framework of understanding, with implications for improving uptake of services. Five focus groups (four to six participants per group) comprising 27 women were conducted to theme saturation. Major themes were (a) spiritual and religious beliefs act as barriers towards uptake of screening and genetic testing (b) preference for traditional medicine competes with Western medicine recommendations (c) family and community influence health-related decisions, complexed by differences in intergenerational beliefs creating contrasting attitudes towards screening and prevention. Decisions to participate in breast cancer screening and genetic testing are influenced by cultural, traditional, spiritual/religious, and intergenerational beliefs. Strategies to increase uptake should include acknowledgement and integration of these beliefs into counseling and education and collaboration with key influential Malay stakeholders and leaders.
Publisher: Wiley
Date: 24-01-2018
DOI: 10.1002/PON.4627
Abstract: Reluctance to share hereditary cancer syndrome genetic test results with family is reported among Asian patients. This study aims to explore patient factors influencing result sharing with family, to improve overall testing uptake. Participants were women with a personal/family history of breast and/or ovarian cancer who received a positive, negative, or variant of uncertain significance test result. In-depth interviews were conducted to theme saturation to explore facilitators and barriers for sharing results with family. Grounded theory with thematic analysis was applied in analysis and interpretation. Twenty-four women participated. Three themes representing facilitators emerged for all results categories: family closeness, involvement of families in the testing process, and perception of low emotional impact of results. In the positive result category, 2 facilitator themes emerged: presence of actionable results and perception of family members' acceptance. In the negative and variant of uncertain significance result categories, 2 themes representing barriers to sharing emerged: perception of no genetic or medical implication for family and result ambiguity. Facilitators and barriers for result sharing are similar to those among Western women. A framework to explain Asian patients' decision-making process identifies optimal counselling opportunities to enhance communication with family.
Publisher: BMJ
Date: 23-12-2017
DOI: 10.1136/JMEDGENET-2017-105073
Abstract: Germline mutations in the BRCA 1 and BRCA 2 genes have significant clinical implications for both risk-reducing and early surveillance management. The third and most recent revision of the Manchester scoring system (MSS3) used to distinguish patients indicated for germline BRCA1/2 testing included further adjustments for triple negative breast cancer, high-grade serous ovarian cancer and human epidermal growth factor 2 (HER2) receptor status. This study aims to evaluate the relative effectiveness of MSS3 in a Southeast Asian population. All patients in our centre were tested using next-generation sequencing (NGS) panels that included full gene sequencing as well as coverage for large deletions/duplications in BRCA1/2 . We calculated MSS1-3 scores for index patients between 2014 and 2017 who had undergone BRCA1/2 genetic testing and recorded their genetic test results. MSS1-3 outcomes were compared using receiver operating characteristic analysis, while associations with predictors were investigated using Fisher’s exact test and logistics regression. Calculations were performed using Medcalc17. Of the 330 included patients, 47 (14.2%) were found to have a germline mutation in BRCA1 or BRCA2 . A positive HER2 receptor was associated with a lower likelihood of a BRCA1/2 mutation (OR=0.125, 95% CI 0.016 to 0.955 P=0.007), while high-grade serous ovarian cancer was conversely associated with an increased likelihood of a BRCA1/2 mutation (OR=5.128, 95% CI 1.431 to 18.370 P=0.012). At the 10% threshold, 43.0% (142/330) of patients were indicated for testing under MSS3, compared with 35.8% (118/330) for MSS1% and 36.4% (120/330) for MSS2. At the 10% threshold, MSS3 sensitivity was 91.5% and specificity 65.0%, significantly better than the previous MSS1 (P = 0.037) and MSS2 (P = 0.032) models. Our results indicate that the updated MSS3 outperforms previous iterations and relative to the Manchester population, is just as effective in identifying patients with BRCA1/2 mutations in a Southeast Asian population.
No related grants have been discovered for Eliza Courtney.