Multinational, Multicenter Evaluation of Prostate Cancer Tissue in Sub-Saharan Africa: Challenges and Opportunities.

PURPOSE: Prostate cancer disproportionately affects men of African descent, yet their representation in tissue-based studies is limited. This multinational, multicenter pilot study aims to establish the groundwork for collaborative research on prostate cancer in sub-Saharan Africa. METHODS: The Men of African Descent and Carcinoma of the Prostate network formed a pathologist working group representing eight institutions in five African countries. Formalin-fixed paraffin-embedded prostate tissue specimens were collected from Senegal, Nigeria, and Ghana. Histology slides were produced and digitally scanned. A central genitourinary pathologist (P.L.) and eight African general pathologists reviewed anonymized digital whole-slide images for International Society of Urological Pathology grade groups and other pathologic parameters. Discrepancies were re-evaluated, and consensus grading was assigned. A virtual training seminar on prostate cancer grading was followed by a second assessment on a subcohort of the same tissue set. RESULTS: Of 134 tissue blocks, 133 had evaluable tissue; 13 lacked cancer evidence, and four were of insufficient quality. Post-training, interobserver agreement for grade groups improved to 56%, with a median Cohen's quadratic weighted kappa of 0.83 (mean, 0.74), compared with an initial 46% agreement and a quadratic weighted kappa of 0.77. Interobserver agreement between African pathologist groups was 40%, with a quadratic weighted kappa of 0.66 (95% CI, 0.51 to 0.76). African pathologists tended to overgrade (36%) more frequently than undergrade (18%) compared with the reference genitourinary pathologist. Interobserver variability tended to worsen with a decrease in tissue quality. CONCLUSION: Tissue-based studies on prostate cancer in men of African descent are essential for a better understanding of this common disease. Standardized tissue handling protocols are crucial to ensure good tissue quality and data. The use of digital slide imaging can enhance collaboration among pathologists in multinational, multicenter studies.

Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men.

Androgenetic alopecia is a highly heritable trait. However, much of our understanding about the genetics of male pattern baldness comes from individuals of European descent. Here, we examined a novel dataset comprising 2,136 men from Ghana, Nigeria, Senegal, and South Africa that were genotyped using a custom array. We first tested how genetic predictions of baldness generalize from Europe to Africa, finding that polygenic scores from European GWAS yielded AUC statistics that ranged from 0.513 to 0.546, indicating that genetic predictions of baldness in African populations performed notably worse than in European populations. Subsequently, we conducted the first African GWAS of androgenetic alopecia, focusing on self-reported baldness patterns at age 45. After correcting for present age, population structure, and study site, we identified 266 moderately significant associations, 51 of which were independent (p-value < 10-5, r2 < 0.2). Most baldness associations were autosomal, and the X chromosomes does not appear to have a large impact on baldness in African men. Finally, we examined the evolutionary causes of continental differences in genetic architecture. Although Neanderthal alleles have previously been associated with skin and hair phenotypes, we did not find evidence that European-ascertained baldness hits were enriched for signatures of ancient introgression. Most loci that are associated with androgenetic alopecia are evolving neutrally. However, multiple baldness-associated SNPs near the EDA2R and AR genes have large allele frequency differences between continents. Collectively, our findings illustrate how evolutionary history contributes to the limited portability of genetic predictions across ancestries.

Testing the generalizability of ancestry-specific polygenic risk scores to predict prostate cancer in sub-Saharan Africa.

BACKGROUND: Genome-wide association studies do not always replicate well across populations, limiting the generalizability of polygenic risk scores (PRS). Despite higher incidence and mortality rates of prostate cancer in men of African descent, much of what is known about cancer genetics comes from populations of European descent. To understand how well genetic predictions perform in different populations, we evaluated test characteristics of PRS from three previous studies using data from the UK Biobank and a novel dataset of 1298 prostate cancer cases and 1333 controls from Ghana, Nigeria, Senegal, and South Africa. RESULTS: Allele frequency differences cause predicted risks of prostate cancer to vary across populations. However, natural selection is not the primary driver of these differences. Comparing continental datasets, we find that polygenic predictions of case vs. control status are more effective for European individuals (AUC 0.608-0.707, OR 2.37-5.71) than for African individuals (AUC 0.502-0.585, OR 0.95-2.01). Furthermore, PRS that leverage information from African Americans yield modest AUC and odds ratio improvements for sub-Saharan African individuals. These improvements were larger for West Africans than for South Africans. Finally, we find that existing PRS are largely unable to predict whether African individuals develop aggressive forms of prostate cancer, as specified by higher tumor stages or Gleason scores. CONCLUSIONS: Genetic predictions of prostate cancer perform poorly if the study sample does not match the ancestry of the original GWAS. PRS built from European GWAS may be inadequate for application in non-European populations and perpetuate existing health disparities.

Is Schistosomiasis a Risk Factor for Bladder Cancer? Evidence-Based Facts.

Background . Globally, approximately 20% of malignancy are caused by infection. Schistosoma infection is a major cause of bladder in most part of Africa. In 2018 alone, there were approximately 549,393 new cases and 199,922 deaths from bladder cancer. The presence of Schistosoma ova in the venous plexus of the bladder induces a cascade of inflammation causing significant tissue damage and granulomatous changes. Methodology. A literature review was conducted from 1995 to 2019 using PubMed, Google Scholar, African Journal Online, and Google databases. Relevant data on the association of "Schistosomiasis and Bladder cancer" in sub-Saharan Africa (SSA) were retrieved. Evidence Synthesis. Results from research using animal models to establish the carcinogenesis of Schistosoma and bladder cancer have been helpful but inconclusive. Immunoregulatory cytokines and genetic marker have been identified to play a role in the pathogenesis. In some parts of sub-Saharan Africa, there has been close association of squamous cell carcinoma and histological evidence of Schistosoma ova. Conclusion. There are some data to support the association between schistosomiasis and bladder cancer in sub-Saharan Africa. However, these have been limited by their design and may not sufficiently establish carcinogenesis. There is a need for more genomic and molecular research to better characterize S. haematobium and its effects on the bladder. Such goal will contribute immensely to Schistosoma bladder cancer prevention and control.

A Custom Genotyping Array Reveals Population-Level Heterogeneity for the Genetic Risks of Prostate Cancer and Other Cancers in Africa.

Although prostate cancer is the leading cause of cancer mortality for African men, the vast majority of known disease associations have been detected in European study cohorts. Furthermore, most genome-wide association studies have used genotyping arrays that are hindered by SNP ascertainment bias. To overcome these disparities in genomic medicine, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a genotyping array that is optimized for African populations. The MADCaP Array contains more than 1.5 million markers and an imputation backbone that successfully tags over 94% of common genetic variants in African populations. This array also has a high density of markers in genomic regions associated with cancer susceptibility, including 8q24. We assessed the effectiveness of the MADCaP Array by genotyping 399 prostate cancer cases and 403 controls from seven urban study sites in sub-Saharan Africa. Samples from Ghana and Nigeria clustered together, whereas samples from Senegal and South Africa yielded distinct ancestry clusters. Using the MADCaP array, we identified cancer-associated loci that have large allele frequency differences across African populations. Polygenic risk scores for prostate cancer were higher in Nigeria than in Senegal. In summary, individual and population-level differences in prostate cancer risk were revealed using a novel genotyping array. SIGNIFICANCE: 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.

Management of Renal Cell Carcinoma-Current Practice in Sub-Saharan Africa.

There is a global variation in the incidence of renal masses with the developed nations having a greater incidence. About 80-90% of renal malignancies are renal cell carcinomas (RCC) which account for 2-4% of all cancers. In Africa and the Middle East, the age-standardized incidence for RCC is 1.8-4.8/100,000 for males and 1.2-2.2/100,000 for females. The management of renal cell cancer is challenging. A multidisciplinary approach is effective for diagnosis, staging, and treatment. Guidelines recommend active surveillance, thermal ablation, partial nephrectomy, radical nephrectomy, cytoreductive nephrectomy and immunotherapy as various modalities for various stages of RCC. However, open radical nephrectomy is most widely adopted as an option for treatment at various stages of the disease in sub-Saharan Africa due to its cost-effectiveness, applicability at various stages, and the reduced cost of follow-up. Nevertheless, most patients in the region present with the disease in the advanced stage and despite surgery the prognosis is poor.

Management of Advanced and Metastatic Prostate Cancer: A Need for a Sub-Saharan Guideline.

The estimated incidence rate of prostate cancer in Africa was 22.0/100,000 in 2016. The International Agency for Research on Cancer (IARC) has cited prostate cancer as a growing health threat in Africa with approximated 28,006 deaths in 2010 and estimated 57,048 deaths in 2030. The exact incidence of advanced and metastatic prostate cancer is not known in sub-Saharan Africa. Hospital-based reports from the region have shown a rising trend with most patients presenting with advanced or metastatic disease. The management of advanced and metastatic prostate cancer is challenging. The available international guidelines may not be cost-effective for an African population. The most efficient approach in the region has been surgical castration by bilateral orchidectomy or pulpectomy. Medical androgen deprivation therapy is expensive and may not be available. Patients with metastatic castrate-resistant prostate cancer tend to be palliated due to the absence or cost of chemotherapy or second-line androgen deprivation therapy in most of Africa. A cost-effective guideline for developing nations to address the rising burden of advanced prostate cancer is warranted at this moment.

A Review of Localized Prostate Cancer: An African Perspective.

Prostate cancer is the second most common malignancy in males and the sixth leading cause of cancer mortality in men with a relatively higher death rate in men of African descent. In the United States and other parts of Europe, more than 80% of diagnosed prostate cancer is localized, and 80-90% of these men receive some form of treatment. The projected data may not be a direct reflection of the disease in the sub-Saharan region as less than 40% presents with localized disease. Results from prostate cancer screening have shown that most African men in the sub-region have little knowledge of the disease. There are recommended international guidelines for the management of localized prostate cancer, however, a guideline in a local context could be ideal.

Non-Muscle Invasive Bladder Cancer: A Review of the Current Trend in Africa.

Bladder cancer is the fourth most common cancer in men and the 11th most common cancer in woman accounting for 6.6% of all cancer cases. Approximately 70-75% bladder cancers are non-muscle invasive bladder cancer (NMIBC). A few African studies have provided considerable rates of NMIBC as compared to western settings 70% to 85%. Critical step in the management of NMIBC is to prevent tumor recurrence which include transurethral resection of the bladder tumor (TURBT) for staging and histological diagnosis. A second TURBT for high grade tumor, T1 tumors and intravesical adjuvant chemotherapy and immunotherapy are essential to reduce recurrence rate. Nevertheless, variant histology, multiple, progressive and recurrent high-grade tumors are best treated with early radical cystectomy. The African literature is scanty on the management of NMIBC. Most of the histological types are squamous cell bladder cancer and may not conform to transurethral resection only but rather radical cystectomy. Most of these patients are not suitable for any form of treatment as they present with advanced disease. However, there is an increasing incidence of urothelial cancer in Africa over the years due to urbanization. It is best that major investment is made in uro-oncological care to address the growing challenge of these subtypes.

180° congenital penile torsion with distal hypospadias mistaken for an epispadias: Optimal outcome with tubularized incised plate urethroplasty and dartos flap rotation.

INTRODUCTION: Severe penile torsion of 180° associated with hypospadias is a rare entity. Knowledge of penile anatomy and pathology are necessary as the diagnosis could be missed. CASE PRESENTATION: We report a case of severe 180° penile torsion with distal hypospadias that was mistaken for an epispadias which was corrected with surgery. CONCLUSION: Tubularized incised plate urethroplasty and dartos flap rotation provided satisfactory result for this association.

Diagnosis, Treatment and Outcome of Gestational Trophoblastic Neoplasia in a Low Resource Income Country.

BACKGROUND AND INTRODUCTION: Gestational trophoblastic disease (GTD) is a disease of the proliferative trophoblastic allograft. Diagnosis and treatment of GTN in low resource-income countries is challenging due to numerous factors. The objective of this study was to review outcomes of gestational trophoblastic neoplasia in women of low socioeconomic status with limited resources and social support. METHODS: This study was performed at Gynecologic and Obstetric Clinic of Dakar Teaching Hospital, the reference Centre of Gestational trophoblastic diseases in Senegal from 2006 to 2015. RESULTS: Out of 1088 patients followed for gestational trophoblastic disease during the study period, 108 patients were diagnosed and treated for GTN: 88 low-risk and 20 high-risk. Low-risk patients received an average of 6.9 cycles of initial single-agent chemotherapy. Twelve patients had persistent disease and were switched to a second line multi-agent chemotherapy. Finally 94.3% of low-risk patients achieved remission. All high-risk patients were initially treated with multi-agent chemotherapy, averaging 7 cycles. Five of the eighty-eight low-risk patients and twelve of the 20 high-risk patients died of disease. CONCLUSION AND GLOBAL HEALTH IMPLICATIONS: Early adequate treatment ensures an excellent prognosis for patients with GTN. In low-income countries, difficulties encountered in diagnosis and treatments worsen the prognosis of GTN patients. Clinical trials are needed to find out affordable schedules or drugs for a better treatment.

Global patterns of prostate cancer incidence, aggressiveness, and mortality in men of african descent.

Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

Androgen Metabolism Gene Polymorphisms, Associations with Prostate Cancer Risk and Pathological Characteristics: A Comparative Analysis between South African and Senegalese Men.

Prostate cancer is the most common cancer in men in developed countries and the leading cause of mortality in males in less developed countries. African ethnicity is one of the major risk factors for developing prostate cancer. Pathways involved in androgen metabolism have been implicated in the etiology of the disease. Analyses of clinical data and CYP3A4, CYP3A5, and SRD5A2 genotypes were performed in South African White (120 cases; 134 controls), Mixed Ancestry (207 cases; 167 controls), and Black (25 cases; 20 controls) men, as well as in Senegalese men (86 cases; 300 controls). Senegalese men were diagnosed earlier with prostate cancer and had higher median PSA levels compared to South African men. Metastasis occurred more frequently in Senegalese men. Gene polymorphism frequencies differed significantly between South African and Senegalese men. The CYP3A4 rs2740574 polymorphism was associated with prostate cancer risk and tumor aggressiveness in South African men, after correction for population stratification, and the SRD5A2 rs523349 CG genotype was inversely associated with high-stage disease in Senegalese men. These data suggest that variants previously associated with prostate cancer in other populations may also affect prostate cancer risk in African men.

A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta.

PURPOSE: Deficiency of prolyl 3-hydroxylase 1, encoded by LEPRE1, causes recessive osteogenesis imperfecta (OI). We previously identified a LEPRE1 mutation exclusively in African Americans and contemporary West Africans. We hypothesized that this allele originated in West Africa and was introduced to the Americas with the Atlantic slave trade. We aimed to determine the frequency of carriers for this mutation among African Americans and West Africans, and the mutation origin and age. METHODS: Genomic DNA was screened for the mutation using PCR and restriction digestion, and a custom TaqMan genomic single-nucleotide polymorphism assay. The mutation age was estimated using microsatellites and short tandem repeats spanning 4.2 Mb surrounding LEPRE1 in probands and carriers. RESULTS: Approximately 0.4% (95% confidence interval: 0.22-0.68%) of Mid-Atlantic African Americans carry this mutation, estimating recessive OI in 1/260,000 births in this population. In Nigeria and Ghana, 1.48% (95% confidence interval: 0.95-2.30%) of unrelated individuals are heterozygous carriers, predicting that 1/18,260 births will be affected with recessive OI, equal to the incidence of de novo dominant OI. The mutation was not detected in Africans from surrounding countries. All carriers shared a haplotype of 63-770 Kb, consistent with a single founder for this mutation. Using linkage disequilibrium analysis, the mutation was estimated to have originated between 650 and 900 years before present (1100-1350 CE). CONCLUSION: We identified a West African founder mutation for recessive OI in LEPRE1. Nearly 1.5% of Ghanians and Nigerians are carriers. The estimated age of this allele is consistent with introduction to North America via the Atlantic slave trade (1501-1867 CE).

Screening for Prostate Cancer by Digital Rectal Examination and PSA Determination in Senegal.

Objectives. The goal of our study was to investigate the prevalence of prostate cancer in an unselected population of Senegalese men. Patients and Methods. We conducted the study over two years (2008 and 2009) on an unselected population of 572 Senegalese men, aged 35 and older. The following parameters have been investigated: the subject's age, the presence or absence of urination disorders, the family's history of prostate cancer or prostate surgery, the aspects of the prostate on digital rectal examination (DRE), the total PSA level, and the outcomes of the prostate biopsies. Data entry was performed with Epi Info 6 software and was analyzed and recorded using Excel software. We performed mean and frequency calculations. Results. The mean age of our patients was 65.5 years, with extremes of 38 and 93 years. Age groups from 50 to 59 and from 60 to 69 were the most represented. DRE was normal in the age group from 35 to 39, and only one patient in the age group from 40 to 49 had a prostate nodule. PSA level was greater than or equal to 4 ng/mL in 66 cases. A total of 5.4% patients had a PSA level greater than or equal to 10 ng/mL. Only two patients in the age group from 40 to 49 had a PSA level greater than 4 ng/mL. Of the 72 biopsies we performed, prostatic adenocarcinoma was found in 30.6% of the cases. It is the only type of prostate cancer we found in our series. The cases of prostate cancer were mostly observed in the age groups from 60 to 69 and from 70 to 79. No cases were detected for ages younger than 50. DRE gave indications of possible adenocarcinoma in 27.30% cases. Its sensitivity was 27%, while its positive predictive value was estimated at 35%. Of all positive biopsies, 4.5% had a PSA level between 0 and 3.9 ng/mL. In this case, the sensitivity of PSA was 95.5%, and the positive predictive value was 31.8%. High-grade intraepithelial neoplasiae were observed in 21 cases. Conclusion. Prostate cancer is frequent in Senegal, and screening remains the best way for early diagnosis.

Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21.

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10(-13)). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.

Evaluation of group genetic ancestry of populations from Philadelphia and Dakar in the context of sex-biased admixture in the Americas.

BACKGROUND: Population history can be reflected in group genetic ancestry, where genomic variation captured by the mitochondrial DNA (mtDNA) and non-recombining portion of the Y chromosome (NRY) can separate female- and male-specific admixture processes. Genetic ancestry may influence genetic association studies due to differences in individual admixture within recently admixed populations like African Americans. PRINCIPAL FINDINGS: We evaluated the genetic ancestry of Senegalese as well as European Americans and African Americans from Philadelphia. Senegalese mtDNA consisted of approximately 12% U haplotypes (U6 and U5b1b haplotypes, common in North Africa) while the NRY haplotypes belonged solely to haplogroup E. In Philadelphia, we observed varying degrees of admixture. While African Americans have 9-10% mtDNAs and approximately 31% NRYs of European origin, these results are not mirrored in the mtDNA/NRY pools of European Americans: they have less than 7% mtDNAs and less than 2% NRYs from non-European sources. Additionally, there is <2% Native American contribution to Philadelphian African American ancestry and the admixture from combined mtDNA/NRY estimates is consistent with the admixture derived from autosomal genetic data. To further dissect these estimates, we have analyzed our samples in the context of different demographic groups in the Americas. CONCLUSIONS: We found that sex-biased admixture in African-derived populations is present throughout the Americas, with continual influence of European males, while Native American females contribute mainly to populations of the Caribbean and South America. The high non-European female contribution to the pool of European-derived populations is consistently characteristic of Iberian colonization. These data suggest that genomic data correlate well with historical records of colonization in the Americas.

Evaluation of prostate cancer characteristics in four populations worldwide.

INTRODUCTION: Prostate cancer is common around the world, but rates of advanced disease differ substantially by race and geography. Although a major health issue, little is known about prostate cancer presentation in West Africa and India compared to the United States (US). OBJECTIVE: The aim of this study was to compare prostate tumor characteristics in four populations of men from the US, Senegal and India. MATERIALS AND METHODS: We recruited prostate cancer patients from four hospital-based populations. The sample included 338 African-Americans, 1265 European-Americans, 122 Asian Indians, and 72 Senegalese. Questionnaire and medical record data were collected on each participant. RESULTS: We found significant differences in age at diagnosis, BMI, and PSA levels across the groups. Senegalese and Indian men had a higher probability of high stage (T3/T4) disease compared to US men. Gleason grade was significantly higher in Asian Indians compared to other populations. African-Americans, Senegalese, and Asian Indians had a significantly higher probability of metastatic disease compared to European Americans. The odds ratios (OR) for metastasis were consistently higher in Asian Indians compared to American cases. As only 19/72 Senegalese were assessed for metastasis, OR could not be determined for metastasis. CONCLUSIONS: These results suggest that there are significant geographical and ethnic differences in the presentation of prostate cancer. Men in developing countries tend to present with advanced disease compared to US men. Identifying risk factors for advanced disease may help to decrease the rate of poor prostate cancer outcomes and associated mortality worldwide.

Genetic susceptibility to prostate cancer in men of African descent: implications for global disparities in incidence and outcomes.

INTRODUCTION: Disparities in prostate cancer incidence and outcomes are a hallmark of the global pattern of prostate cancer, with men of African descent suffering disproportionately from this disease. The causes of these disparities are poorly understood. METHODS: A review of the literature was undertaken to evaluate the role that genetic susceptibility may play in prostate cancer etiology and outcomes, with a particular emphasis on disparities. RESULTS: The genetic contribution to prostate cancer is well established, and a number of candidate prostate cancer genes have been identified. Significant differences in the frequency of risk alleles in these genes have been identified across the major races. These allele frequency differences may in part explain an increased susceptibility to prostate cancer in some populations. In addition, non-genetic factors contribute significantly to prostate cancer disparities, and the cumulative contribution of both genetic and non-genetic factors to poor-prognosis prostate cancer may explain the poorer outcomes experienced by men of African descent. CONCLUSIONS: Prostate cancer disparities are a function of genetic susceptibility as well as environment, behavior, and health care factors acting in the context of this genetic susceptibility. Elimination of global prostate cancer disparities requires a full understanding of the effects of all of these factors on prostate cancer etiology and outcomes.