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.

Pituitary gland trauma in fatal nonsurgical closed traumatic brain injury.

BACKGROUND: Traumatic injury to pituitary gland can lead to significant endocrine dysfunctions. The aim of this study is to define the frequency of pituitary gland injury in patients with fatal nonsurgical closed traumatic brain injury (TBI), and to correlate if any, the type of craniocerebral injury associated with the pituitary gland injury. METHODS: The study is a prospective autopsy review of 30 adult patients with fatal closed TBI. Patients who had any form of neurosurgical intervention were excluded from the study. The harvested pituitary glands were assessed morphologically and histologically with haematoxylin-eosin stains. RESULTS: There were 25 males and five females (median age: 35 years). Fatal closed TBI was associated with at least pituitary stalk rupture or pituitary gland haemorrhage in 13 patients (43.3%). There was significant relationship between subdural haemorrhage (SH) and either pituitary gland haemorrhage or pituitary stalk rupture. Odds ratio (OR) of a patient with SH having accompanying glandular pituitary haemorrhage was 21 while the OR of a patient with SH having pituitary stalk rupture was 12. CONCLUSION: Pituitary gland haemorrhage and stalk rupture frequency are fairly common in fatal closed TBI that do not require surgical intervention. Injury to both structures probably plays substantial roles in closed TBI outcome. We suggest routine assessment of pituitary gland function test in patients with closed TBI associated with SH.

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.

Custodial deaths seen in the Office of the Chief Medical Examiner, Lagos, Nigeria: An 11-year autopsy study.

INTRODUCTION: Deaths in custody are a matter of global concern. However, such information is often missing in developing countries. This study aimed to examine retrospectively the profile, cause and manner of deaths amongst cases of custodial deaths in Lagos State, Nigeria. METHOD: An 11-year study (June 2008-June 2019) was done of all autopsy cases of custodial deaths in the Office of the Chief Medical Examiner. Variables including age, sex, offence, place of death, duration in custody prior to death and cause and manner of death were extracted from the records. Results were analysed using frequencies and percentages. RESULTS: Out of 9894 autopsies over the study period, 45 custodial deaths were identified. Males and females constituted 84.4% and 15.6%, respectively (M:F = 5.4:1). Ages ranged from 20 to 64 years, with a mean age of 37 ± 11.0 years. These deaths were most common in the third decade. Armed robbery and financial crime were the two leading reasons for arrest, while most deaths occurred within 24 hours of arrival in custody. The two leading causes of death were acute cardiac failure from hypertensive heart disease and cranio-cerebral injury from blunt-force trauma. CONCLUSION: Deaths in custody need to be properly investigated and particular attention needs to be paid to unlawful deaths if and when they arise.

Pathology Services in Nigeria: Cross-Sectional Survey Results From Three Cancer Consortia.

PURPOSE: Cancer incidence is increasing in sub-Saharan Africa, yet there is little information on the capacity of pathology laboratories in this region. We aimed to assess the current state of pathology services in Nigeria to guide strategies to ensure best practices and improve the quality of surgical specimen handling. METHODS: We developed structured pathology survey to assess tissue handling, sample processing, and immunohistochemistry (IHC) capabilities. The survey was distributed electronically to 22 medical centers in Nigeria that are part of established cancer consortia. Data were collected between September and October 2017. RESULTS: Sixteen of 22 centers completed the survey in full. All 16 institutions had at least one board-certified pathologist and at least one full-time laboratory scientist/technologist. The majority of responding institutions (75%) reported processing fewer than 3,000 samples per year. For sample processing, 38% of institutions reported manual tissue processing and 75% processed biopsies and surgical specimens together. The average tissue fixation time ranged from 5 to more than 72 hours before processing and paraffin embedding. Half of the institutions reported having no quality assurance processes to evaluate hematoxylin and eosin-stained slides, and 25% reported having no written operating procedures. Half of the participating institutions have a facility for routine IHC staining, and among these there was considerable variability in processes and validation procedures. External proficiency testing was not common among surveyed sites (38%). CONCLUSION: Data from 16 Nigerian medical institutions indicate deficiencies in standardization, quality control, and IHC validation that could affect the reliability of pathology results. These findings highlight addressable gaps in pathology services that can ensure accurate diagnosis and follow-up for the growing number of patients with cancer in this region.

Gastrointestinal autonomic nerve tumours--report of a case and review of literature.

BACKGROUND: Gastrointestinal autonomic nerve tumours are uncommon stromal tumours of the intestinal tract. They can involve any part of the gastrointestinal system, but are very rarely seen in the rectum. CASE PRESENTATION: We report a unique case of rectal schwannoma with associated synchronous adenocarcinoma of the splenic flexure and adenoma of the descending colon. A 70-year-old patient was admitted with complaint of bleeding per rectum and investigations revealed the presence of a large submucosal rectal lesion in addition to the colonic pathologies. Following panproctocolectomy with permanent spout ileostomy, histopathology and immunohistochemistry confirmed the rectal lesion to be a schwannoma. CONCLUSION: Literature review of the few reported cases has suggested radical surgical excision to be the best approach. Prognosis tends to be favourable after resection.