ORCID Profile
0000-0002-0817-2574
Current Organisation
South African Medical Research Council
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Publisher: Wiley
Date: 10-12-2015
DOI: 10.1002/PROS.23126
Publisher: MDPI AG
Date: 08-06-2010
Publisher: Springer Science and Business Media LLC
Date: 04-06-2019
Publisher: Cold Spring Harbor Laboratory
Date: 04-04-2018
Abstract: Genomic rearrangements are common in cancer, with demonstrated links to disease progression and treatment response. These rearrangements can be complex, resulting in fusions of multiple chromosomal fragments and generation of derivative chromosomes. Although methods exist for detecting in idual fusions, they are generally unable to reconstruct complex chained events. To overcome these limitations, we adopted a new optical mapping approach, allowing megabase-length genome maps to be reconstructed and rearranged genomes to be visualized without loss of integrity. Whole-genome mapping (Bionano Genomics) of a well-studied highly rearranged liposarcoma cell line resulted in 3338 assembled consensus genome maps, including 72 fusion maps. These fusion maps represent 112.3 Mb of highly rearranged genomic regions, illuminating the complex architecture of chained fusions, including content, order, orientation, and size. Spanning the junction of 147 chromosomal translocations, we found a total of 28 Mb of interspersed sequences that could not be aligned to the reference genome. Traversing these interspersed sequences using short-read sequencing breakpoint calls, we were able to identify and place 399 sequencing fragments within the optical mapping gaps, thus illustrating the complementary nature of optical mapping and short-read sequencing. We demonstrate that optical mapping provides a powerful new approach for capturing a higher level of complex genomic architecture, creating a scaffold for renewed interpretation of sequencing data of particular relevance to human cancer.
Publisher: MDPI AG
Date: 07-05-2020
Abstract: Background: While critical insights have been gained from evaluating the genomic landscape of metastatic prostate cancer, utilizing this information to inform personalized treatment is in its infancy. We performed a retrospective pilot study to assess the current impact of precision medicine for locally advanced and metastatic prostate adenocarcinoma and evaluate how genomic data could be harnessed to in idualize treatment. Methods: Deep whole genome-sequencing was performed on 16 tumour-blood pairs from 13 prostate cancer patients whole genome optical mapping was performed in a subset of 9 patients to further identify large structural variants. Tumour s les were derived from prostate, lymph nodes, bone and brain. Results: Most s les had acquired genomic alterations in multiple therapeutically relevant pathways, including DNA damage response (11/13 cases), PI3K (7/13), MAPK (10/13) and Wnt (9/13). Five patients had somatic copy number losses in genes that may indicate sensitivity to immunotherapy (LRP1B, CDK12, MLH1) and one patient had germline and somatic BRCA2 alterations. Conclusions: Most cases, whether primary or metastatic, harboured therapeutically relevant alterations, including those associated with PARP inhibitor sensitivity, immunotherapy sensitivity and resistance to androgen pathway targeting agents. The observed intra-patient heterogeneity and presence of genomic alterations in multiple growth pathways in in idual cases suggests that a precision medicine model in prostate cancer needs to simultaneously incorporate multiple pathway-targeting agents. Our whole genome approach allowed for structural variant assessment in addition to the ability to rapidly reassess an in idual’s molecular landscape as knowledge of relevant biomarkers evolve. This retrospective oncological assessment highlights the genomic complexity of prostate cancer and the potential impact of assessing genomic data for an in idual at any stage of the disease.
Publisher: Hindawi Limited
Date: 2007
DOI: 10.1002/HUMU.20533
Abstract: Analysis of SNPs for association, linkage, haplotype, and pharmacogenetic studies has led to a dramatic increase in the number and evolution of medium- to high-throughput genotyping technologies. This study introduces Plexor as a new method for medium-throughput (single SNP) genotyping. We compare this fluorescent-based chemistry for call rate, accuracy, affordability, throughput, and overall efficiency against two commonly used technologies. These include fluorescent-based TaqMan allelic discrimination for single SNP analysis (medium-throughput) and the homogenous MassEXTEND (hME) chemistry using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for multiple SNP analysis (high-throughput). Analysis of 11 SNPs, including all six possible nucleotide substitutions, showed Plexor to be highly comparable for both call rate (94.7%) and accuracy (99.2%) to the TaqMan (94.6% and 99.8%, respectively) and hME (91.9% and 98.1%, respectively) chemistries. We demonstrate that this novel method is an efficient, cost-effective alternative to TaqMan genotyping commonly used in diagnostic settings.
Publisher: Impact Journals, LLC
Date: 05-10-2016
Publisher: Public Library of Science (PLoS)
Date: 14-03-2013
Publisher: Wiley
Date: 14-11-2018
DOI: 10.1002/PROS.23440
Abstract: Mitochondrial genome (mtDNA) content is depleted in many cancers. In prostate cancer, there is intra-glandular as well as inter-patient mtDNA copy number variation. In this study, we determine if mtDNA content can be used as a predictor for prostate cancer staging and outcomes. Fresh prostate cancer biopsies from 115 patients were obtained at time of surgery. All cores underwent pathological review, followed by isolation of cancer and normal tissue. DNA was extracted and qPCR performed to quantify the total amount of mtDNA as a ratio to genomic DNA. Differences in mtDNA content were compared for prostate cancer pathology features and disease outcomes. We showed a significantly reduced mtDNA content in prostate cancer compared with normal adjacent prostate tissue (mean difference 1.73-fold, P-value <0.001). Prostate cancer with increased mtDNA content showed unfavorable pathologic characteristics including, higher disease stage (PT2 vs PT3 P-value = 0.018), extracapsular extension (P-value = 0.02) and a trend toward an increased Gleason score (P-value = 0.064). No significant association was observed between changes in mtDNA content and biochemical recurrence (median follow up of 107 months). Contrary to other cancer types, prostate cancer tissue shows no universally depleted mtDNA content. Rather, the change in mtDNA content is highly variable, mirroring known prostate cancer genome heterogeneity. Patients with high mtDNA content have an unfavorable pathology, while a high mtDNA content in normal adjacent prostate tissue is associated with worse prognosis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2001
DOI: 10.1097/00002030-200101260-00005
Abstract: Most mutations detected for the gene for CC chemokine receptor 5 (CCR5) are either relatively specific to different population groups or rarely observed in Africans. To develop a comprehensive mutation detection assay for the entire coding region of CCR5 and to identify novel mutations that may play a role in genetic susceptibility to HIV-1 infection, within the erse South African population. The study cohort consisted of 103 HIV-seropositive patients and 146 HIV-seronegative controls of predominantly African descent. A mutation detection assay for the entire coding region of CCR5 was designed this included lification of part of the coding region of CCR2. The assay was based on denaturing gradient gel electrophoresis (DGGE) and allowed the complete analysis of s les from 10 in iduals per denaturing gel. The use of the CCR5-DGGE assay led to the identification of seven novel and six previously reported mutations. All novel mutations, including a common polymorphism at codon 35, occurred exclusively in non-Caucasians, indicating possible African origin. A comprehensive DGGE mutation detection assay has been developed for the entire coding region of CCR5. Application of this assay resulted in the identification of novel CCR5 mutations, which may have a significant effect on the normal functioning of CCR5 and thus contribute to host variability and susceptibility to HIV-1 infection and/or progression to AIDS within this population.
Publisher: Impact Journals, LLC
Date: 03-2017
Publisher: American Association for Cancer Research (AACR)
Date: 13-12-2018
DOI: 10.1158/0008-5472.CAN-18-0254
Abstract: The first whole-genome sequencing study for high-risk prostate cancer in African men allows a simultaneous comparison of ethnic differences relative to European populations and of the influences of the environment relative to African-American men.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2018
DOI: 10.1200/JGO.18.00062
Abstract: Health research in low- and middle-income countries can generate novel scientific knowledge and improve clinical care, fostering population health improvements to prevent premature death. Project management is a critical part of the success of this research, applying knowledge, skills, tools, and techniques to accomplish required goals. Here, we describe the development and implementation of tools to support a multifaceted study of prostate cancer in Africa, focusing on building strategic and operational capacity. Applying a learning organizational framework, we developed and implemented a project management toolkit (PMT) that includes a management process flowchart, a cyclical center-specific schedule of activities, periodic reporting and communication, and center-specific monitoring and evaluation metrics. The PMT was successfully deployed during year one of the project with effective component implementation occurring through periodic cycles of dissemination and feedback to local center project managers. A specific evaluation was conducted 1 year after study initiation to obtain enrollment data, evaluate in idual quality control management plans, and undertake risk log assessments and follow-up. Pilot data obtained identified areas in which centers required mentoring, strengthening, and capacity development. Strategies were implemented to improve project goals and operational capacity through local problem solving, conducting quality control checks and following compliancy with study aims. Moving forward, centers will perform quarterly evaluations and initiate strengthening measures as required. The PMT has fostered the development of both strategic and operational capacity across project centers. Investment in project management resources is essential to ensuring high-quality, impactful health research in low- and middle-income countries.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2020
DOI: 10.1158/0008-5472.CAN-19-2165
Abstract: This study presents an Africa-specific genotyping array, which enables investigators to identify novel disease associations and to fine-map genetic loci that are associated with prostate and other cancers.
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.VIROL.2006.06.031
Abstract: TRIM5alpha acts on several retroviruses, including human immunodeficiency virus (HIV-1), to restrict cross-species transmission. Using natural history cohorts and tissue culture systems, we examined the effect of polymorphism in human TRIM5alpha on HIV-1 infection. In African Americans, the frequencies of two non-coding SNP variant alleles in exon 1 and intron 1 of TRIM5 were elevated in HIV-1-infected persons compared with uninfected subjects. By contrast, the frequency of the variant allele encoding TRIM5alpha 136Q was relatively elevated in uninfected in iduals, suggesting a possible protective effect. TRIM5alpha 136Q protein exhibited slightly better anti-HIV-1 activity in tissue culture than the TRIM5alpha R136 protein. The 43Y variant of TRIM5alpha was less efficient than the H43 variant at restricting HIV-1 and murine leukemia virus infections in cultured cells. The ancestral TRIM5 haplotype specifying no observed variant alleles appeared to be protective against infection, and the corresponding wild-type protein partially restricted HIV-1 replication in vitro. A single logistic regression model with a permutation test indicated the global corrected P value of <0.05 for both SNPs and haplotypes. Thus, polymorphism in human TRIM5 may influence susceptibility to HIV-1 infection, a possibility that merits additional evaluation in independent cohorts.
Publisher: Hindawi Limited
Date: 24-09-2002
DOI: 10.1002/HUMU.10111
Abstract: A single nucleotide polymorphism (SNP) at codon 64 in the CC chemokine receptor 2 gene (CCR2 V64I) has been associated with a dominant effect of delaying disease progression from human immunodeficiency virus-1 (HIV-1) infection to acquired immunodeficiency syndrome (AIDS). The objective of our study was to design a comprehensive mutation detection assay for the entire coding region of the CCR2A and CCR2B gene transcripts, including all relevant splice site junctions and to identify novel mutations and SNPs within our predominantly African-based population, which could influence an in idual's susceptibility to HIV-1 infection and/or progression to AIDS. The mutation detection assay, based on denaturing gradient gel electrophoresis (DGGE), allowed for the complete analysis of five in iduals per denaturing gel. Our study cohort consisted of 102 HIV seropositive patients and 144 HIV seronegative controls from the erse South African population. Application of the CCR2-DGGE assay resulted in the detection of two previously reported CCR2 polymorphisms, namely CCR2 V64I and CCR2 N260N, and 11 novel mutations, including seven SNPs occurring at high allelic frequencies within specific population groups of South Africa. The large number of novel mutations/SNPs identified, using the CCR2-DGGE assay, indicates the importance for comprehensive analysis of all candidate genes in host susceptibility to HIV-1 infection, specifically in the under-studied African-based populations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2002
Publisher: Springer Science and Business Media LLC
Date: 02-2010
DOI: 10.1038/NATURE08795
Publisher: Springer Science and Business Media LLC
Date: 13-12-2022
Publisher: American Association for Cancer Research (AACR)
Date: 12-0001
DOI: 10.1158/1055-9965.EPI-08-0896
Abstract: There is growing evidence that inflammation and infection play important roles in the etiology of prostate cancer. As the chemokine network is directly involved in inflammation and infectious diseases, we tested for an association between six common putative functional variants and prostate cancer risk using an Australian case-control study. We measured CCL5 −403G& A, CXCL12 +801G& A, CCR2V64I (G& A), CCR5Δ32, CX3CR1V249I (G& A), and CX3CR1T280M (C& T) for 815 cases and 738 controls. Of these, only CXCL12 +801G& A has previously been tested and found to be associated with prostate cancer risk. We found no significant associations with prostate cancer risk (all P & 0.4). All per allele odds ratios ranged from 0.96 (95% confidence intervals, 0.80-1.16) to 1.06 (95% confidence intervals, 0.90-1.23). This suggests that these common chemokine and chemokine receptor variants do not play a major, if any, role in susceptibility to prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008 (12):3615–7)
Publisher: Wiley
Date: 11-2009
DOI: 10.1002/JMV.21601
Abstract: Susceptibility for human immunodeficiency virus type 1 (HIV-1) infection may be influenced by host genetics. Recent findings with a Wistar rat model raised the possibility that the gamma-secretase pathway may be associated with an in idual's susceptibility to infection. A functional single-nucleotide polymorphism (SNP) in the gamma-secretase component APH1B (Phe217Leu rs1047552) was therefore analyzed for association with HIV-1 infection. The SNP showed a tendency for association with HIV-1 infection in a Xhosa indigenous South African Bantu study (P = 0.087), and associated significantly in a Caucasian Dutch study (P = 0.049). Together, the results suggest a role for the gamma-secretase pathway in susceptibility to HIV-1 infection.
Publisher: Oxford University Press (OUP)
Date: 20-11-2019
DOI: 10.1634/THEONCOLOGIST.2019-0590
Abstract: Current literature is inconsistent in the associations between computed tomography (CT)-based body composition measures and adverse outcomes in older patients with colorectal cancer (CRC). Moreover, the associations with consecutive treatment modalities have not been studied. This study compared the associations of CT-based body composition measures with surgery- and chemotherapy-related complications and survival in older patients with CRC. A retrospective single-center cohort study was conducted in patients with CRC aged ≥65 years who underwent elective surgery between 2010 and 2014. Gender-specific standardized scores of preoperative CT-based skeletal muscle (SM), muscle density, intermuscular adipose tissue (IMAT), visceral adipose tissue (VAT), subcutaneous adipose tissue, IMAT percentage, SM/VAT, and body mass index (BMI) were tested for their associations with severe postoperative complications, prolonged length of stay (LOS), readmission, and dose-limiting toxicity using logistic regression and 1-year and long-term survival (range 3.7–6.6 years) using Cox regression. Bonferroni correction was applied to account for multiple testing. The study population consisted of 378 patients with CRC with a median age of 73.4 (interquartile range 69.5–78.4) years. Severe postoperative complications occurred in 13.0%, and 39.4% of patients died during follow-up. Dose-limiting toxicity occurred in 77.4% of patients receiving chemotherapy (n = 53). SM, muscle density, VAT, SM/VAT, and BMI were associated with surgery-related complications, and muscle density, IMAT, IMAT percentage, and SM/VAT were associated with long-term survival. After Bonferroni correction, no CT-based body composition measure was significantly associated with adverse outcomes. Higher BMI was associated with prolonged LOS. The associations between CT-based body composition measures and adverse outcomes of consecutive treatment modalities in older patients with CRC were not consistent or statistically significant.
Publisher: Proceedings of the National Academy of Sciences
Date: 27-06-2011
Abstract: The Tasmanian devil ( Sarcophilus harrisii ) is threatened with extinction because of a contagious cancer known as Devil Facial Tumor Disease. The inability to mount an immune response and to reject these tumors might be caused by a lack of genetic ersity within a dwindling population. Here we report a whole-genome analysis of two animals originating from extreme northwest and southeast Tasmania, the maximal geographic spread, together with the genome from a tumor taken from one of them. A 3.3-Gb de novo assembly of the sequence data from two complementary next-generation sequencing platforms was used to identify 1 million polymorphic genomic positions, roughly one-quarter of the number observed between two genetically distant human genomes. Analysis of 14 complete mitochondrial genomes from current and museum specimens, as well as mitochondrial and nuclear SNP markers in 175 animals, suggests that the observed low genetic ersity in today's population preceded the Devil Facial Tumor Disease disease outbreak by at least 100 y. Using a genetically characterized breeding stock based on the genome sequence will enable preservation of the extant genetic ersity in future Tasmanian devil populations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-12-2005
DOI: 10.1097/01.QAI.0000186360.42834.28
Abstract: CXC chemokine ligand 12 (CXCL12), or stromal cell-derived factor 1 (SDF1), is the only known natural ligand for the HIV-1 coreceptor, CXC chemokine receptor 4 (CXCR4). A single nucleotide polymorphism (SNP) in the CXCL12 gene (SDF1-3'A) has been associated with disease progression to AIDS in some studies, but not others. Mutations in the CXCR4 gene are generally rare and have not been implicated in HIV-1/AIDS pathogenesis. This study analyzed the SDF1-3'A SNP and performed mutation screening for polymorphic markers in the CXCR4 gene to determine the presence or absence of significant associations with susceptibility to HIV-1 infection. The study consisted of 257 HIV-1-seropositive patients and 113 HIV-1-seronegative controls representing a sub-Saharan African population belonging to the Xhosa ethnic group of South Africa. The SDF1-3'A SNP was associated with an increased risk for HIV-1 infection (P = 0.0319) whereas no significant association was observed between the occurrence of the SDF1-3'A SNP and increased or decreased plasma levels of CXCL12. Comprehensive mutation analysis of the CXCR4 gene confirmed a high degree of genetic conservation within the coding region of this ancient population.
Publisher: Public Library of Science (PLoS)
Date: 25-03-2015
Publisher: Wiley
Date: 09-04-2014
DOI: 10.1002/PROS.22806
Publisher: Hindawi Limited
Date: 06-2009
DOI: 10.1002/HUMU.20919
Abstract: Mutation detection has, until recently, relied heavily on the use of gel-based methods that can be both time consuming and difficult to design. Nongel-based systems are therefore important to increase simplicity and improve turn around time without compromising assay sensitivity and accuracy, especially in the diagnostic/clinical setting. In this study, we assessed the latest of the nongel-based methods, namely high-resolution melt (HRM) curve analysis. HRM is a closed-tube method that incorporates a saturating dye during DNA lification followed by a monitoring of the change in fluorescence as the DNA duplex is denatured by an increasing temperature. We assessed 10 licons derived from eight genes, namely SERPINA1, CXCR7, MBL, VDR, NKX3A, NPY, TP53, and HRAS using two platforms, the LightScanner System using LC Green PLUS DNA binding dye (Idaho Technology, Salt Lake City, UT, USA) and the LightCycler 480 using the HRM Master dye (Roche Diagnostics, Indianapolis, IN, USA). DNA variants (mutations or polymorphims) were previously identified using denaturing gradient gel electrophoresis (DGGE) a method, similarly to HRM, based upon the different melting properties of double-stranded DNA. Fragments were selected based on variant and fragment complexity. This included the presence of multiple sequence variants, variants in alternate orientations, and single or multiple variants (constitutional or somatic) in GC-rich fragments. We demonstrate current limitations of the HRM method for the analysis of complex DNA regions and call for caution when using HRM as the sole method to make a clinical diagnosis based on genetic analysis.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 10-2021
Publisher: Oxford University Press (OUP)
Date: 05-11-2009
DOI: 10.1093/HMG/DDP505
Abstract: STATEMENT: In naming population groups, we think a chief aim is to use terms that the group members use themselves, or find familiar and comfortable. The terms used in this manuscript to describe populations are as historically correct as possible and are chosen so as not to offend any population group. Two of the authors (DCP and REvdR) belong to the Coloured population, with one of the authors (REvdR) having contributed extensively to current literature on the history of the Coloured people of South Africa and served as Vice-President of the South African Institute of Race Relations. According to the 2001 South African census (www.statssa.gov.za/census01/HTML/CInBrief/CIB2001.pdf), "Statistics South Africa continues to classify people by population group, in order to monitor progress in moving away from the apartheid-based discrimination of the past. However, membership of a population group is now based on self-perception and self-classification, not on a legal definition. Five options were provided on the questionnaire, Black African, Coloured, Indian or Asian, White and Other. Responses in the category 'Other' were very few and were therefore imputed". We have elected to use the term Bushmen rather than San to refer to the hunter-gatherer people of Southern Africa. Although they have no collective name for themselves, this decision was based on the term Bushmen (or Bossiesman) being the more familiar to the communities themselves, while the term San is the more accepted academic classification. Understanding human genetic structure has fundamental implications for understanding the evolution and impact of human diseases. In this study, we describe the complex genetic substructure of a unique and recently admixed population arising approximately 350 years ago as a direct result of European settlement in South Africa. Analysis was performed using over 900 000 genome-wide single nucleotide polymorphisms in 20 unrelated ancestry-informative marker selected Coloured in iduals and made comparisons with historically predicted founder populations. We show that there is substantial genetic contribution from at least four distinct population groups: Europeans, South Asians, Indonesians and a population genetically close to the isiXhosa sub-Saharan Bantu. This is in good accord with the historical record. We briefly examine the implications of determining the genetic ersity of this population, not only for furthering understanding of human evolution out of Africa, but also for genome-wide association studies using admixture mapping. In conclusion, we define the genetic structure of a uniquely admixed population that holds great potential to advance genetic-based medical research.
Publisher: Springer Science and Business Media LLC
Date: 28-10-2019
DOI: 10.1038/S41586-019-1714-1
Abstract: Anatomically modern humans originated in Africa around 200 thousand years ago (ka)
Publisher: Springer Science and Business Media LLC
Date: 22-02-2010
No related grants have been discovered for Desiree Petersen.