Whole-exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways.

BACKGROUND: Through whole-exome sequencing of 60 formalin-fixed paraffin-embedded Nigerian (NGRn) benign prostatic hyperplasia (BPH) samples, we identified germline and somatic alterations in apoptotic pathways impacting BPH development and progression. Prostate enlargement is a common occurrence in male aging; however, this enlargement can lead to lower urinary tract symptoms that negatively impact quality of life. This impact is disproportionately present in men of African ancestry. BPH pathophysiology is poorly understood and studies examining non-European populations are lacking. METHODS: In this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH. RESULTS: Two hundred and two nonbenign, ClinVar-annotated germline variants were present in NGRn BPH samples. Six genes [BRCA1 (92%), HSD3B1 (85%), TP53 (37%), PMS2 (23%), BARD1 (20%), and BRCA2 (17%)] were altered in at least 10% of samples; however, compared to NGRn normal and tumor, the frequency of alterations in BPH samples showed no significant differences at the gene or variant level. BRCA2_rs11571831 and TP53_rs1042522 germline alterations had a statistically significant co-occurrence interaction in BPH samples. In at least two BPH samples, 173 genes harbored somatic variants known to be clinically actionable. Three genes (COL18A1, KIF16B, and LRP1) showed a statistically significant (p < 0.05) higher frequency in BPH. NGRn BPH also had five gene pairs (PKD1/KIAA0100, PKHD1/PKD1, DNAH9/LRP1B, NWD1/DCHS2, and TCERG1/LMTK2) with statistically significant co-occurring interactions. Two hundred and seventy-nine genes contained novel somatic variants in NGRn BPH. Three genes (CABP1, FKBP1C, and RP11-595B24.2) had a statistically significant (p < 0.05) higher alteration frequency in NGRn BPH and three were significantly higher in NGRn tumor (CACNA1A, DMKN, and CACNA2D2). Pairwise Fisher's exact tests showed 14 gene pairs with statistically significant (p < 0.05) interactions and four interactions approaching significance (p < 0.10). Mutational patterns in NGRn BPH were similar to COSMIC (Catalog of Somatic Mutations in Cancer) signatures associated with aging and dysfunctional DNA damage repair. CONCLUSIONS: NGRn BPH contained significant germline alteration interactions (BRCA2_rs11571831 and TP53_rs1042522) and increased somatic alteration frequencies (LMTK2, LRP1, COL18A1, CABP1, and FKBP1C) that impact apoptosis. Normal prostate development is maintained by balancing apoptotic and proliferative activity. Dysfunction in either mechanism can lead to abnormal prostate growth. This work is the first to examine genomic sequencing in NGRn BPH and provides data that fill known gaps in the understanding BPH and how it impacts men of African ancestry.

Satisfaction with high-resolution anoscopy for anal cancer screening among men who have sex with men: a cross-sectional survey in Abuja, Nigeria.

BACKGROUND: Men who have sex with men (MSM) living with HIV are at increased risk for anal cancer. We evaluated satisfaction with first-time anal cancer screening using high resolution anoscopy (HRA) as a cross sectional survey among men who have sex with men (MSM) attending a community-engaged clinic in Abuja, Nigeria. METHODS: Between March and August 2017, 342 MSM underwent screening and 307 (89%) completed a satisfaction survey that evaluated 8 domains related to expectations, convenience, staff interpersonal skills, physical surroundings, technical competence, pain/discomfort, general satisfaction, and intention to re-screen if symptomatic. The 22-item questionnaire used 5-point Likert scales ranging from 1 (strongly disagree) to 5 (strongly agree). For each domain, responses to specific items were averaged, aggregated, and converted to a 100-point scaled score (SS) with 25 and 75 corresponding to disagree and agree, respectively. RESULTS: Median age was 24 years (interquartile range [IQR]: 22-28), median years since anal coital debut was 7 (IQR: 4-12), and 58% (95% confidence interval [CI]: 52-64%) were living with HIV. Despite respondents reporting pre-procedure anxiety (SS:73), most were comfortable with the setting and procedure and reported overall satisfaction (SS:74-76). Willingness to undergo future screening had the lowest score (SS:69) within the general satisfaction domain. The lowest scoring domains were pain/discomfort (SS:57) and agreement to re-screen if symptomatic (SS:59), which correlated with lower overall satisfaction (p < 0.001). Domain responses did not differ by HIV infection after adjusting for multiple comparisons (p > 0.006) or number of anal biopsies (all p > 0.05). CONCLUSIONS: Overall, HRA was satisfactory for those naïve to screening but moving forward necessitates monitoring levels of discomfort with pain scales and normalizing dialogue around clinical symptoms of anal cancer and overall anal health to sustain future screening.

Whole-exome Sequencing of Nigerian Prostate Tumors from the Prostate Cancer Transatlantic Consortium (CaPTC) Reveals DNA Repair Genes Associated with African Ancestry.

In this study, we used whole-exome sequencing of a cohort of 45 advanced-stage, treatment-naïve Nigerian (NG) primary prostate cancer tumors and 11 unmatched nontumor tissues to compare genomic mutations with African American (AA) and European American (EA) The Cancer Genome Atlas (TCGA) prostate cancer. NG samples were collected from six sites in central and southwest Nigeria. After whole-exome sequencing, samples were processed using GATK best practices. BRCA1 (100%), BARD1 (45%), BRCA2 (27%), and PMS2(18%) had germline alterations in at least two NG nontumor samples. Across 111 germline variants, the AA cohort reflected a pattern [BRCA1 (68%), BARD1 (34%), BRCA2 (28%), and PMS2 (16%)] similar to NG samples. Of the most frequently mutated genes, BRCA1 showed a statistically (P ≤ 0.05) higher germline mutation frequency in men of African ancestry (MAA) and increasing variant frequency with increased African ancestry. Disaggregating gene-level mutation frequencies by variants revealed both ancestry-linked and NG-specific germline variant patterns. Driven by rs799917 (T>C), BRCA1 showed an increasing mutation frequency as African ancestry increased. BRCA2_rs11571831 was present only in MAA, and BRCA2_rs766173 was elevated in NG men. A total of 133 somatic variants were present in 26 prostate cancer-associated genes within the NG tumor cohort. BRCA2 (27%), APC (20%), ATM (20%), BRCA1 (13%), DNAJC6 (13%), EGFR (13%), MAD1L1 (13%), MLH1 (11%), and PMS2 (11%) showed mutation frequencies >10%. Compared with TCGA cohorts, NG tumors showed statistically significant elevated frequencies of BRCA2, APC, and BRCA1. The NG cohort variant pattern shared similarities (cosign similarities ≥0.734) with Catalogue of Somatic Mutations in Cancer signatures 5 and 6, and mutated genes showed significant (q < 0.001) gene ontology (GO) and functional enrichment in mismatch repair and non-homologous repair deficiency pathways. Here, we showed that mutations in DNA damage response genes were higher in NG prostate cancer samples and that a portion of those mutations correlate with African ancestry. Moreover, we identified variants of unknown significance that may contribute to population-specific routes of tumorigenesis and treatment. These results present the most comprehensive characterization of the NG prostate cancer exome to date and highlight the need to increase diversity of study populations. Significance: MAA have higher rates of prostate cancer incidence and mortality, however, are severely underrepresented in genomic studies. This is the first study utilizing whole-exome sequencing in NG men to identify West African ancestry-linked variant patterns that impact DNA damage repair pathways.

Correlation of Clinical, Endoscopic, and Pathological Findings among Suspected Peptic Ulcer Disease Patients in Abuja, Nigeria.

BACKGROUND: Peptic ulcer disease (PUD) remains one of the most prevalent gastrointestinal diseases and has been linked to Helicobacter pylori (H. pylori) infection. This condition may be suspected on clinical grounds, but diagnosis is established using upper gastrointestinal endoscopy. AIMS: To determine the correlation between the endoscopic and pathological findings among suspected PUD patients who have been referred for diagnostic upper gastrointestinal endoscopy in National Hospital Abuja. METHODS: This is a hospital-based prospective study conducted among suspected PUD patients at National Hospital Abuja over a one-year period. Clinical, endoscopic, and histological findings were ascertained and documented. Data obtained were analyzed using SPSS version 21.0. Tests of significance were done using the chi-square test and Student t-test at 95% confidence intervals. RESULTS: One hundred and thirty-two patients were included in the study. The ages ranged from 15 to 87 years, mean age 43.30 ± 11.94 years. Seventy-seven (58.3%) patients had abnormal endoscopic findings, of whom 37 (28.0%) had PUD. Prevalence of H. pylori infection was 42.2% and was found in 81.1% of PUD patients. H. pylori was significantly associated with confirmed PUD (p < 0.001) and abnormal endoscopic findings (p < 0.001). No association was found between normal endoscopic findings and histological findings (p = 0.924). CONCLUSION: There is a poor correlation between clinical and endoscopic diagnoses of PUD. H. pylori was found to be significantly associated with PUD and abnormal endoscopic findings. Endoscopic facilities should therefore be made available and accessible for proper PUD diagnosis. Empirical treatment of H. pylori in patients with diagnosed PUD is strongly recommended.

Invasive Pulmonary Cryptococcal Infection Masquerading as Lung Cancer with Brain Metastases: A Case Report.

Cryptococcosis, a global disease problem, seen frequently in the immuno-suppressed, also affects patients without apparent immuno-suppression. Pulmonary cryptococcosis patients often present as cryptococcal pneumonia, whereas intracranial cryptococcosis presents with meningitis. We present a 33-year-old immunocompetent man, diagnosed with invasive pulmonary cryptococcal disease with spread to the brain. This case is unique because the patient was previously treated for tuberculosis and presented with typical bronchopulmonary thoracic, extra-thoracic as well as computed tomography (CT) scan features suggestive of lung cancer. Cryptococcosis was diagnosed by identification of oval thick-walled yeast on histology of lung biopsy specimen. The patient was treated with flucytosine and fluconazole initially and subsequently with Amphotericin B and fluconazole. He made clinical improvement with the resolution of symptoms but had residual radiological features. Invasive cryptococcosis affecting the lung and brain may present with a clinical picture similar to metastatic lung cancer. We recommend routine fungal stains and fungal culture in suspected cases.

La cryptococcose, une maladie mondiale, fréquemment observée chez les sujets immunodéprimés, affecte également les patients sans immunodépression apparente. Les patients atteints de cryptococcose pulmonaire se présentent souvent comme une pneumonie cryptococcique tandis que la cryptococcose intracrânienne se présente avec une méningite. Nous présentons un homme immunocompétent de 33 ans, diagnostiqué avec une maladie pulmonaire invasive cryptococcique avec propagation au cerveau. Ce cas est unique car le patient a déjà été traité pour tuberculose et s'est présenté avec des caractéristiques bronchopulmonaires thoraciques, extra-thoraciques ainsi qu'une tomodensitométrie (TDM) typiques suggérant un cancer du poumon. La cryptococcose a été diagnostiquée par l'identification d'une levure ovale à paroi épaisse sur l'histologie d'un échantillon de biopsie pulmonaire. Le patient a été traité initialement par Flucytosine et Fluconazole, puis par Amphotéricine B et Fluconazole. Il a fait une amélioration clinique avec la résolution des symptômes mais avait des caractéristiques radiologiques résiduelles. La cryptococcose invasive affectant le poumon et le cerveau peut présenter un tableau clinique similaire au cancer du poumon métastatique. Nous recommandons des colorations fongiques de routine et une culture fongique dans les cas suspects.

Multiple HPV infections among men who have sex with men engaged in anal cancer screening in Abuja, Nigeria.

BACKGROUND: Anal precancers and cancers can be detected during screening with high-resolution anoscopy (HRA). The sensitivity of HRA depends on the burden and duration of human papillomavirus (HPV) among those screened as well as anoscopist proficiency, which is highly correlated with prior screening experience. Our objective was to compare the identification and type of HPV and the likelihood of HRA-detected precancer for men who have sex with men (MSM) undergoing their first HRA-screening in Nigeria. METHODS: MSM were recruited from an HIV test-and-treat cohort, TRUST/RV368, into a new anal cancer screening program. Anal swabs obtained during screening underwent Ion Torrent next-generation sequencing using barcoded HPV PCR broad-spectrum primers 5+/6+ to detect up to 161 HPVs. All high-risk (HR) HPVs and the most abundant low-risk (LR)-HPVs were evaluated as type-specific infections with some categorized as belonging to a multiple infection. HRA screening results included benign, low-grade squamous intraepithelial lesions (LSIL), or HSIL as detected by cytology or histology. Multivariable logistic regression was used to assess the association of HPV and other cofactors with any SIL. RESULTS: Among 342 MSM, 60% were HIV-infected, 89% were under 35 years of age, and 51% had 8 or more years since anal coital debut. Of those with SIL, 89% had LSIL and only 11% had HSIL. Prevalence of any HPV and high-risk (HR)-HPV was 92% and 74%, respectively. The most prevalent genotypes in rank order were HPV6 (31%), HPV16 (23%), HPV42 (20%), HPV11 (18%), HPV45 (18%), and HPV51 (17%). For multiple HR-HPVs, 31% had a single HR-HPV, 32% had 2-3, and 10% had 4 or more. Low-risk HPVs, type 6 and/or 11, were common (42%) and were significantly associated with SIL (adjusted odds ratio [aOR]:1.8, 95% confidence interval [CI]: 1.1-3.1) together with perianal warts (aOR:6.7, 95% CI: 3.3-13.5). In contrast, HR-HPV and multiple HR-HPVs were not significantly associated with SIL (all p > 0.05). CONCLUSIONS: Detection of HSIL was low. Although HR-HPV was abundant, HSIL development also depends on the duration of HR-HPV infections and the anoscopist's level of experience. As our cohort ages and the anoscopist becomes more skilled, detection of HSIL will likely improve.

Gene Expression Profiling Analysis Reveals Putative Phytochemotherapeutic Target for Castration-Resistant Prostate Cancer.

Prostate cancer is the leading cause of cancer death among men globally, with castration development resistant contributing significantly to treatment failure and death. By analyzing the differentially expressed genes between castration-induced regression nadir and castration-resistant regrowth of the prostate, we identified soluble guanylate cyclase 1 subunit alpha as biologically significant to driving castration-resistant prostate cancer. A virtual screening of the modeled protein against 242 experimentally-validated anti-prostate cancer phytochemicals revealed potential drug inhibitors. Although, the identified four non-synonymous somatic point mutations of the human soluble guanylate cyclase 1 gene could alter its form and ligand binding ability, our analysis identified compounds that could effectively inhibit the mutants together with wild-type. Of the identified phytochemicals, (8'R)-neochrome and (8'S)-neochrome derived from the Spinach (Spinacia oleracea) showed the highest binding energies against the wild and mutant proteins. Our results identified the neochromes and other phytochemicals as leads in pharmacotherapy and as nutraceuticals in management and prevention of castration-resistance prostate cancers.

Implementation of and Early Outcomes From Anal Cancer Screening at a Community-Engaged Health Care Facility Providing Care to Nigerian Men Who Have Sex With Men.

PURPOSE: Anal cancer risk is substantially higher among HIV-infected men who have sex with men (MSM) as compared with other reproductive-age adults, but screening is rare across sub-Saharan Africa. We report the use of high-resolution anoscopy (HRA) as a first-line screening tool and the resulting early outcomes among MSM in Abuja, Nigeria. METHODS: From August 2016 to August 2017, 424 MSM enrolled in an anal cancer screening substudy of TRUST/RV368, a combined HIV prevention and treatment cohort. HRA-directed biopsies were diagnosed by histology, and ablative treatment was offered for high-grade squamous intraepithelial lesions (HSIL). HRA proficiency was assessed by evaluating the detection of squamous intraepithelial lesions (SIL) over time and the proportion biopsied. Prevalence estimates of low-grade squamous intraepithelial lesions and HSIL with 95% CIs were calculated. Multinomial logistic regression was used to identify those at the highest risk of SIL. RESULTS: Median age was 25 years (interquartile range [IQR], 22-29), median time since sexual debut was 8 years (IQR, 4-12), and 59% (95% CI, 54.2% to 63.6%) were HIV infected. Rate of detection of any SIL stabilized after 200 screenings, and less than 20% had two or more biopsies. Preliminary prevalence estimates of low-grade squamous intraepithelial lesions and HSIL were 50.0% (95% CI, 44.7% to 55.3%) and 6.3% (95% CI, 4.0% to 9.3%). HIV infection, at least 8 years since anal coital debut, concurrency, and external warts were independently statistically associated with SIL. CONCLUSION: Proficiency with HRA increased with experience over time. However, HSIL detection rates were low, potentially affected by obstructed views from internal warts and low biopsy rates, highlighting the need for ongoing evaluation and mentoring to validate this finding. HRA is a feasible first-line screening tool at an MSM-friendly health care facility. Years since anal coital debut and external warts could prioritize screening.

Histo-pathological pattern of intracranial tumours in the National Hospital, Abuja.

BACKGROUND/AIMS: Intracranial tumours demonstrate characteristic diagnostic histopathological features. Our aims were to look at the histo-pathological pattern of intracranial tumours in our environment including their age and sex distribution. METHODS: The histology request forms and slides of all intracranial specimens submitted to the histo-pathology department of National Hospital, Abuja, over an 11 year period (2005 and 2015) were retrospectively reviewed. RESULTS: Intracranial specimens and intracranial tumours accounted for 0.6% and 0.5% respectively of all samples submitted. Meningiomas accounted for the most frequent diagnosis for all intracranial specimens and intracranial tumours at 35% and 41% respectively followed by pituitary adenoma at 19% and 22%, and astrocytoma at 13% and 20%. The male female ratio for all diagnoses was 1:1. The mean age at diagnosis was 35 ± 17.1 years. The frequency of intracranial tumours in children was 11.8% with a mean age of 8.3 ± 4.4 years and an equal sex distribution. In children, glioma and embryonal tumours were the most frequent diagnosis at 25%. CONCLUSION: The histo-pathological pattern of intracranial tumours in our environment showed that meningioma is the most common intracranial tumour in adults, while glioma and embryonal tumours are the most common intracranial tumours in children.