ORCID Profile
0000-0002-8485-6556
Current Organisation
University of Sydney
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Research Square Platform LLC
Date: 31-03-2023
DOI: 10.21203/RS.3.RS-2715972/V1
Abstract: BACKGROUND: Prostate cancer (PCa) is a significant health burden for African men, with mortality rates more than double global averages. The prostate specific Anoctamin 7 ( ANO7 ) gene linked with poor patient outcomes, has recently been identified as the target for an African-specific protein-truncating PCa risk allele. METHODS: Here we determined the role of ANO7 in a study of 889 men from southern Africa, leveraging exomic genotyping array PCa case-control data (n=780, 17 ANO7 alleles) and deep sequenced whole genome data for germline and tumour ANO7 interrogation (n=109), while providing clinicopathologically matched European derived sequence data comparative analyses (n=57). Associated predicted deleterious variants (PDVs) were further assessed for impact using computational protein structure analysis. RESULTS: Notably rare in European patients, we found the common African PDV p.Ile740Leu variant (rs74804606) to be associated with PCa risk in our case-control analysis (Wilcoxon rank-sum test, false discovery rate/FDR=0.03), while sequencing revealed cooccurrence with the recently reported African-specific deleterious risk variant p.Ser914* (rs60985508). Additional findings include, a novel protein truncating African-specific frameshift variant p.Asp789Leu, African-relevant PDVs associated with altered protein structure at Ca 2+ -binding sites, early-onset PCa associated with PDVs and germline structural variants in Africans (Linear regression models, -6.42 years, 95% CI=-10.68 to -2.16, P -value=0.003) and ANO7 as an inter-chromosomal PCa-related gene fusion partner in African derived tumours. CONCLUSIONS: Here we provide not only validation for ANO7 as an African-relevant protein-altering PCa risk locus, but additional evidence for a role of inherited and acquired ANO7 variance in the observed phenotypic heterogeneity and African ancestral health disparity.
Publisher: Elsevier BV
Date: 07-2023
Publisher: Springer Science and Business Media LLC
Date: 18-03-2021
DOI: 10.1038/S41598-021-85262-X
Abstract: Maintaining genetic ersity in dog breeds is an important consideration for the management of inherited diseases. We evaluated genetic ersity in Border Collies using molecular and genealogical methods, and examined changes to genetic ersity when carriers for Trapped Neutrophil Syndrome (TNS) and Neuronal Ceroid Lipofuscinosis (NCL) are removed from the genotyped population. Genotype data for 255 Border Collies and a pedigree database of 83,996 Border Collies were used for analysis. Molecular estimates revealed a mean multi-locus heterozygosity (MLH) of 0.311 (SD 0.027), 20.79% of the genome consisted of runs of homozygosity (ROH ) 1 Mb, effective population size ( N e ) was 84.7, and mean inbreeding (F) was 0.052 (SD 0.083). For 227 genotyped Border Collies that had available pedigree information (GenoPed), molecular and pedigree estimates of ersity were compared. A reference population (dogs born between 2005 and 2015, inclusive N = 13,523 RefPop) and their ancestors (N = 12,478) were used to evaluate the ersity of the population that are contributing to the current generation. The reference population had a N e of 123.5, a mean F of 0.095 (SD 0.082), 2276 founders ( f ), 205.5 effective founders ( f e ), 28 effective ancestors ( f a ) and 10.65 (SD 2.82) founder genomes ( N g ). Removing TNS and NCL carriers from the genotyped population had a small impact on ersity measures (ROH 1 Mb, MLH, heterozygosity), however, there was a loss of 10% minor allele frequency for 89 SNPs around the TNS mutation (maximum loss of 12.7%), and a loss of 5% for 5 SNPs around the NCL mutation (maximum 5.18%). A common ancestor was identified for 38 TNS-affected dogs and 64 TNS carriers, and a different common ancestor was identified for 33 NCL-affected dogs and 28 carriers, with some overlap of prominent in iduals between both pedigrees. Overall, Border Collies have a high level of genetic ersity compared to other breeds.
Publisher: Harborside Press, LLC
Date: 03-2023
Abstract: Background: Germline testing for prostate cancer is on the increase, with clinical implications for risk assessment, treatment, and management. Regardless of family history, NCCN recommends germline testing for patients with metastatic, regional, very-high-risk localized, and high-risk localized prostate cancer. Although African ancestry is a significant risk factor for aggressive prostate cancer, due to a lack of available data no testing criteria have been established for ethnic minorities. Patients and Methods: Through deep sequencing, we interrogated the 20 most common germline testing panel genes in 113 Black South African males presenting with largely advanced prostate cancer. Bioinformatic tools were then used to identify the pathogenicity of the variants. Results: After we identified 39 predicted deleterious variants (16 genes), further computational annotation classified 17 variants as potentially oncogenic (12 genes 17.7% of patients). Rare pathogenic variants included CHEK2 Arg95Ter, BRCA2 Trp31Arg, ATM Arg3047Ter (2 patients), and TP53 Arg282Trp. Notable oncogenic variants of unknown pathogenicity included novel BRCA2 Leu3038Ile in a patient with early-onset disease, whereas patients with FANCA Arg504Cys and RAD51C Arg260Gln reported a family history of prostate cancer. Overall, rare pathogenic and early-onset or familial-associated oncogenic variants were identified in 6.9% (5/72) and 9.2% (8/87) of patients presenting with a Gleason score ≥8 or ≥4 + 3 prostate cancer, respectively. Conclusions: In this first-of-its-kind study of southern African males, we provide support of African inclusion for advanced, early-onset, and familial prostate cancer genetic testing, indicating clinical value for 30% of current gene panels. Recognizing current panel limitations highlights an urgent need to establish testing guidelines for men of African ancestry. We provide a rationale for considering lowering the pathologic diagnostic inclusion criteria and call for further genome-wide interrogation to ensure the best possible African-relevant prostate cancer gene panel.
Publisher: MDPI AG
Date: 19-09-2023
Publisher: Wiley
Date: 2019
DOI: 10.1111/AVJ.12780
Abstract: The aims of this study were to (1) describe the results of a survey on the clinical features of lymphoma in Australian Border Collies and (2) investigate familial clustering of lymphoma-affected dogs by means of pedigree analyses. Clinical and pedigree information was collected from surveys completed by owners or breeders of Australian Border Collies. Relationships between dogs were derived from pedigree data and kinship was analysed by network and cluster-based algorithms. A total of 246 respondents completed the survey and 57 lymphoma-affected Australian Border Collies were identified. The mean age of diagnosis was 9.16 (SD ± 3.43) years and the median was 9.7 years (range 2-15 years). The odds of female dogs affected with lymphoma were twice those of males in the reported data (OR = 2.06 95% CI = 1.13-3.73 P = 0.02). Multicentric, high-grade B-cell lymphoma was the most common form in these dogs. Pedigree analyses identified 21 affected dogs that descended from two sires and 28 cases with a common female ancestor. Average inbreeding between both affected and unaffected dogs was similar (0.16, SD ± 0.06 and 0.15, SD ± 0.06, respectively). The survey confirmed the presence of a relatively large number of cases of lymphoma in Australian Border Collies, consistent with our previous report of increased risk in this breed. Some dogs were diagnosed at a very young age, but the age ranged over the normal lifespan. Pedigree analyses identified multiple cases within family groups, suggesting a heritable component of the disease in this breed.
Publisher: Springer Science and Business Media LLC
Date: 09-2019
DOI: 10.1007/S11306-019-1586-2
Abstract: German shepherd dogs (GSDs) are a popular breed affected by numerous disorders. Few studies have explored genetic variations that influence canine blood metabolite levels. To investigate genetic variants affecting the natural metabolite variation in GSDs. A total of 82 healthy GSDs were genotyped on the Illumina CanineHD Beadchip, assaying 173,650 markers. For each dog, 74 metabolites were measured through liquid and gas chromatography mass spectrometry (LC-MS and GC-MS) and were used as phenotypes for genome-wide association analyses (GWAS). Sliding window and homozygosity analyses were conducted to fine-map regions of interest, and to identify haplotypes and gene dosage effects. Summary statistics for 74 metabolites in this population of GSDs are reported. Forty-one metabolites had significant associations at a false discovery rate of 0.05. Two associations were located around genes which encode for enzymes for the relevant metabolites: 4-hydroxyproline was significantly associated to D-amino acid oxidase (DAO), and threonine to L-threonine 3-dehydrogenase (LOC477365). Three of the top ten haplotypes associated to 4-hydroxyproline included at least one SNP on DAO. These haplotypes occurred only in dogs with the highest 15 measurements of 4-hydroxyproline, ranging in frequency from 16.67 to 20%. None of the dogs were homozygous for these haplotypes. The top two haplotypes associated to threonine included SNPs on LOC477365 and were also overrepresented in dogs with the highest 15 measurements of threonine. These haplotypes occurred at a frequency of 90%, with 80% of these dogs homozygous for the haplotypes. In dogs with the lowest 15 measurements of threonine, the haplotypes occurred at a frequency of 26.67% and 0% homozygosity. DAO and LOC477365 were identified as candidate genes affecting the natural plasma concentration of 4-hydroxyproline and threonine, respectively. Further investigations are needed to validate the effects of the variants on these genes.
Publisher: Research Square Platform LLC
Date: 09-06-2023
DOI: 10.21203/RS.3.RS-2993516/V1
Abstract: African ancestry is a significant risk factor for prostate cancer and advanced disease. Yet, genetic studies have largely been conducted outside the context of Sub-Saharan Africa, identifying 278 common risk variants contributing to a multiethnic polygenic risk score, with rare variants focused on a panel of roughly 20 pathogenic genes. Based on this knowledge, we were unable to determine polygenic risk or differentiate prostate cancer status interrogating whole genome data for 113 Black South African men. To further assess for potentially functional common and rare variant associations, we interrogated 247,780 exomic variants for 798 Black South African men using a case versus control or aggressive versus non-aggressive study design. Notable genes of interest included HCP5 , RFX6 and H3C1 for risk, and MKI67 and KLF5 for aggressive disease. Our study highlights the need for further inclusion across the African diaspora to establish African-relevant risk models aimed at reducing prostate cancer health disparities.
Publisher: Springer Science and Business Media LLC
Date: 25-09-2023
No related grants have been discovered for Pamela Soh.