African-specific molecular taxonomy of prostate cancer.

Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African-European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene-environment interaction-defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa-we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

Warfarin Anticoagulation and Fetal Central Nervous System Abnormalities: a Case Report.

BACKGROUND: Anticoagulation of pregnant woman with mechanical prosthetic heart valves is associated with significant maternal and fetal risks. METHODS: We describe a case of dorsal midline dysplasia in a fetus at 11 weeks' gestation. The mother was receiving warfarin therapy at a dose of 7.5 mg daily following a mechanical mitral valve replacement for rheumatic heart disease. RESULTS: Histological assessment revealed a meningocele with hemorrhage. No cerebellar or cerebral tissue was present in the skull confirming anencephaly. CONCLUSIONS: A multidisciplinary approach in pregnant women with mechanical prosthetic heart valves is essential in order to improve fetal outcomes.

Spectrum of mitochondrial genomic variation and associated clinical presentation of prostate cancer in South African men.

BACKGROUND: Prostate cancer incidence and mortality rates are significantly increased in African-American men, but limited studies have been performed within Sub-Saharan African populations. As mitochondria control energy metabolism and apoptosis we speculate that somatic mutations within mitochondrial genomes are candidate drivers of aggressive prostate carcinogenesis. METHODS: We used matched blood and prostate tissue samples from 87 South African men (77 with African ancestry) to perform deep sequencing of complete mitochondrial genomes. Clinical presentation was biased toward aggressive disease (Gleason score >7, 64%), and compared with men without prostate cancer either with or without benign prostatic hyperplasia. RESULTS: We identified 144 somatic mtDNA single nucleotide variants (SNVs), of which 80 were observed in 39 men presenting with aggressive disease. Both the number and frequency of somatic mtDNA SNVs were associated with higher pathological stage. CONCLUSIONS: Besides doubling the total number of somatic PCa-associated mitochondrial genome mutations identified to date, we associate mutational load with aggressive prostate cancer status in men of African ancestry.

HPV types in cervical cancer tissue in South Africa: A head-to-head comparison by mRNA and DNA tests.

Accurate identification of human papillomavirus (HPV)-types in cervical cancer tissue may be important for tailoring tests for primary screening and types to be included in a vaccine. The aim of this study was to compare test-performance of a 45-type HPV deoxyribonucleic acid (DNA)-test with a 9-type HPV messenger ribonucleic acid (mRNA)-test in cervical cancer tissues.In a case-series design 188 women with diagnosed cervical cancer during the period January 2008 to July 1, 2011 at the Gynaecological Oncology Unit, University of Pretoria, South Africa were recruited to the study. After cases with negative internal controls for DNA/mRNA detection (n = 18) and unconfirmed histology (n = 3) of cervical cancer were excluded, 167 women remained eligible for analysis. We compared 45 DNA-types detected through general primer (GP)5/6 polymerase chain reaction (PCR) and reverse line blot (RLB) genotyping with a modified version of the mRNA test PreTect HPV-Proofer detecting 9 genotypes (16, 18, 31, 33, 35, 45, 51, 52, 58).Histological types were 92.2% squamous cell carcinoma, 4.8% adenocarcinoma, and 3.0% adenosquamous carcinoma. Overall, HPV was detected in 95.2% (159/167) of specimens. The DNA- and mRNA tests each rendered 153/167 (91.6%) HPV positive results. When restricting the analysis to the 9 high-risk HPV-types included in the mRNA test, 91.6% (153/167) and 88.0% (147/167) were positive by the mRNA- and DNA-tests (P = .28), respectively. After hierarchical categorization of 9 comparable types, we found concordance in 66 of 67 specimens for HPV16, 25 of 27 specimens for HPV18, 19 of 21 specimens for HPV45, and only in 33 of 45 for HPV31, 33, 35, 51, 52, 58. The positivity rate for the HPV types 16, 18, and 45 and the positivity rate for HPV 16, 18, 45, 33 and 35 by both tests was 66% to 68% and 80% to 83%, respectively.Overall and when considering established high-risk types, the mRNA test has at least as high detection rate as the DNA test. The mRNA test can be an appropriate research tool to describe causative HPV-types in cervical cancer tissue for health care planning purposes.

Molecular characterisation of gastrointestinal stromal tumours in a South African population.

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the digestive tract. Pathogenesis is linked to activating mutations identified in two proto-oncogenes, v-kit Hardy/Zuckerman 4 feline sarcoma viral oncogene homologue KIT (KIT) and the platelet-derived growth factor α (PDGFRα). In addition, these mutations affect response to treatment with tyrosine kinase inhibitors. In the present study, we report on the molecular characterisation of GISTs in the South African population. Tumour DNA was extracted from 46 GIST samples, followed by cycle sequencing of KIT exons 11, 13 and 17 and PDGFRα exons 12, 14 and 18. Fragment length analysis was used to detect a 6-bp duplication in KIT exon 9. Wild-type duplications were analysed further by PCR and sequencing of additional KIT and PDGFRα exons was performed. Overall, 78.3% of the samples had a mutation in KIT or PDGFRα. Of these, mutations were detected in KIT exon 11 (88.9%), PDGFRα exon 18 (8.3%) and KIT exon 9 (2.8%). Mutations varied from simple substitutions and duplications to large deletions (some with nucleotide insertions) resulting in missense mutations. In addition, seven single nucleotide polymorphisms were detected in 17 patients, one of which appears novel. The incidence of mutations in KIT exon 11 and PDGFRα exon 18 is consistent with the literature, however, the low incidence of KIT exon 9 mutations detected was unexpected. In contrast to previous western and Asian studies, this mutation appears to be rare in the South African population. The present study contributes to the molecular understanding of GISTs in the South African population.

Microscopic diversity in oral Kaposi sarcoma.

Kaposi sarcoma is the most common HIV-associated neoplasm, frequently presenting with oral mucosal involvement. This retrospective study aimed to assess and highlight the histomorphological spectrum of oral Kaposi sarcoma. A total of 135 cases diagnosed between 1990 and 2011 were retrieved from the archives of the Oral and Dental Hospital of the University of Pretoria, South Africa. Following histologic review, each case was placed into 1 of 7 categories based on the predominant pattern of growth. These histologic divisions included lesions designated as solid, lymphangioma-like, telangiectatic, desmoplastic, lymphangiectatic, ecchymotic, and anaplastic. The presence of coexistent pathology was identified in 25 cases, largely represented by superimposed candidiasis. Concomitant cytomegalovirus and non-necrotizing granulomatous inflammation were also observed. Although the prognostic significance of these variants is yet to be determined, the appreciation and recognition of such morphologic diversity remains essential in distinguishing these lesions from possible mimickers.

Gastric cancers of Western European and African patients show different patterns of genomic instability.

BACKGROUND: Infection with H. pylori is important in the etiology of gastric cancer. Gastric cancer is infrequent in Africa, despite high frequencies of H. pylori infection, referred to as the African enigma. Variation in environmental and host factors influencing gastric cancer risk between different populations have been reported but little is known about the biological differences between gastric cancers from different geographic locations. We aim to study genomic instability patterns of gastric cancers obtained from patients from United Kingdom (UK) and South Africa (SA), in an attempt to support the African enigma hypothesis at the biological level. METHODS: DNA was isolated from 67 gastric adenocarcinomas, 33 UK patients, 9 Caucasian SA patients and 25 native SA patients. Microsatellite instability and chromosomal instability were analyzed by PCR and microarray comparative genomic hybridization, respectively. Data was analyzed by supervised univariate and multivariate analyses as well as unsupervised hierarchical cluster analysis. RESULTS: Tumors from Caucasian and native SA patients showed significantly more microsatellite instable tumors (p < 0.05). For the microsatellite stable tumors, geographical origin of the patients correlated with cluster membership, derived from unsupervised hierarchical cluster analysis (p = 0.001). Several chromosomal alterations showed significantly different frequencies in tumors from UK patients and native SA patients, but not between UK and Caucasian SA patients and between native and Caucasian SA patients. CONCLUSIONS: Gastric cancers from SA and UK patients show differences in genetic instability patterns, indicating possible different biological mechanisms in patients from different geographical origin. This is of future clinical relevance for stratification of gastric cancer therapy.

Immunotactoid glomerulonephritis in a child with HIV infection: a case report.

Renal disease is a common complication of human immunodeficiency virus (HIV) infection in adults. In children, however, HIV pathology of the gastrointestinal and respiratory tracts predominates, whereas renal disease is often an incidental finding. In this report, we describe a child with stage III HIV infection associated with immunotactoid glomerulonephritis (IT). The patient was referred for investigation of idiopathic nephrotic syndrome. Electron microscopy of his renal biopsy specimen revealed numerous electron-dense microtubular deposits, arranged in parallel fashion, consistent with a diagnosis of IT. He received highly active antiretroviral therapy (HAART) as well as corticosteroids and is currently in remission. To our knowledge, this is the first report of IT in a child.