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.

Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria.

Somatic mutation signatures may represent footprints of genetic and environmental exposures that cause different cancer. Few studies have comprehensively examined their association with germline variants, and none in an indigenous African population. SomaticSignatures was employed to extract mutation signatures based on whole-genome or whole-exome sequencing data from female patients with breast cancer (TCGA, training set, n = 1,011; Nigerian samples, validation set, n = 170), and to estimate contributions of signatures in each sample. Association between somatic signatures and common single nucleotide polymorphisms (SNPs) or rare deleterious variants were examined using linear regression. Nine stable signatures were inferred, and four signatures (APOBEC C>T, APOBEC C>G, aging and homologous recombination deficiency) were highly similar to known COSMIC signatures and explained the majority (60-85%) of signature contributions. There were significant heritable components associated with APOBEC C>T signature (h2 = 0.575, p = 0.010) and the combined APOBEC signatures (h2 = 0.432, p = 0.042). In TCGA dataset, seven common SNPs within or near GNB5 were significantly associated with an increased proportion (beta = 0.33, 95% CI = 0.21-0.45) of APOBEC signature contribution at genome-wide significance, while rare germline mutations in MTCL1 was also significantly associated with a higher contribution of this signature (p = 6.1 × 10-6 ). This is the first study to identify associations between germline variants and mutational patterns in breast cancer across diverse populations and geography. The findings provide evidence to substantiate causal links between germline genetic risk variants and carcinogenesis.

Autologous Bone Flap Resorption Years After Subtemporal Craniotomy.

In Spring of 2012, the partially undressed and skeletonized remains of a homeless adult Hispanic male was found in a fairly open wooded area in Nebraska. The remains showed evidence of extensive pathologies, which included healed traumas and surgeries. Examination of the decedent's medical records revealed that he had a history of kidney and liver problems, alcohol abuse, several traumas including a major head injury that necessitated a craniotomy, and radiological features of neurocysticercosis. The autologous bone flap, which was replaced after the craniotomy, had resorbed significantly away from the edges of the injury. Death was variously attributed to craniocerebral injury with hypothermia sequel to blunt force trauma most probably due to a fall. The manner of death was ruled as an accident. This study makes use of the forensic evidence and medical records to examine the possibility that the unique combination of failed cranioplasty, hypothermia, and neurocysticercosis may have contributed to the victim's death. Other potential causes of death are considered.

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.

PALEOEPIDEMIOLOGY OF DIPHYLLOBOTHRIOSIS: CULTURAL AND ENVIRONMENTAL FACTORS AFFECTING ADENOCEPHALUS INTENSITY AND PREVALENCE.

Peruvian and Chilean mummies and coprolites provide a source of population-based parasitological information. This is especially true of the fish tapeworm, Adenocephalus pacificus. Our analysis of Chinchorro and Chiribaya mummies and diversified coprolite samples from Chile and Peru show variation in infection. There is a statistically significant difference in prevalence between Chinchorro hunter-gatherer and Chiribaya mixed-subsistence contexts. Furthermore, the most pronounced differences occur between populations within these groups. Chinchorro differences in cemeteries at the same location can be related to El Niño-Southern Oscillation variations. Pronounced prevalence variations between 3 Chiribaya villages within 7 km of each other relate to fish distribution and preparation variation. As with other recent archaeoparasitology studies, eggs-per-gram data exhibit overdispersion.

Trends in motorcycle accident mortality in Lagos: Consequences of government policy changes.

Background: Motorcycle use is associated with fatal crashes. The government of Lagos State, Nigeria has introduced legislation and policies to address this issue. Aim: To examine trends in motorcycle accident mortality in Lagos over a 10-year period (January 2010 - December 2019) and consider the impact of transportation legislation and policy changes on deaths from motorcycle accidents during that period. Method: A retrospective analysis of all autopsies performed on decedents from motorcycle crashes between January 2010 and December 2019. Results: There were 211 cases of motorcycle accident-related deaths. Most victims were males (89.1%), the peak age was 31-40 years (30.8%), and majority were riders and pillion passengers (39.8% each). Head injury (51.6%) was the most common injury and cause of death. There was a general decline in case numbers from 2010 to 2019. Following new legislation that introduced a motorcycle hailing service between 2017 and 2019, there was a 17.4% reduction in fatalities from accidents. Conclusion: There has been a general downward trend in fatal motorcycle accidents in Lagos from 2010 to 2019. Changes in government transportation policies have likely had consequences on motorcycle accident-related mortality.

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.

Right ventricular dysplasia in the elderly: a case report from autopsy.

Right ventricular dysplasia (RVD) is a rare disease of the heart that primarily affects the right ventricle. It is a clinical and pathological entity that presents classically with palpitations, syncope, or even sudden death. It presents rarely in the elderly. Where sudden death is the first and only presentation, an autopsy is required to make the diagnosis. However, the pathomorphological features of RVD can easily be overlooked or missed at autopsy. We report the case of a 68-year-old male with the past medical history of hypertension, gout and inflammatory bowel syndrome. He was admitted on account of difficulty in breathing, abdominal swelling and reduced urination. Physical examination revealed hypertension with cardiac murmurs, widespread crepitations, distended abdomen and lower limb oedema. Provisional diagnoses of acute-on-chronic kidney disease and congestive cardiac failure secondary to hypertensive heart disease, precipitated by probable gastrointestinal infection were made. While on admission, he had an episode of syncope. Electrocardiogram revealed bigeminy and bradycardic sinus rhythm with unifocal ventricular premature contraction. He died on the 8th week of admission. Autopsy revealed an enlarged heart weighing 600gm; there was thinning of the apical aspect of the right ventricular wall with subtotal fibrofatty replacement. Microscopic examination revealed a transmural replacement of cardiac myocytes by fibroadipose tissue extending inwards, in the most parts, from the epicardium to the endocardial surface. Our aim is to increase the awareness of these pathomorphological features among anatomic/forensic pathologists.

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes.

Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.

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.

Author Correction: Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

The original version of this Article contained an error in the author affiliations. The affiliation of Kevin P. White with Tempus Labs, Inc. Chicago, IL, USA was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.

Medical evidence and proof of cause of death in Nigerian courts.

Medical evidence has continued to be given and evaluated in Nigerian courts since Nigeria's independence from Britain. The attitudes of the courts have been largely varied against a background of the individual judge's appreciation of forensic science and who should be considered an expert witness. The prosecution and defence lawyers equally display limited knowledge of forensic science. This paper reviews some of the decided cases, the reasons for the verdicts, forensic concerns and recommendations for the improvement of the criminal justice system. There is need to improve the knowledge base of the bar and the bench.

Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

Racial/ethnic disparities in breast cancer mortality continue to widen but genomic studies rarely interrogate breast cancer in diverse populations. Through genome, exome, and RNA sequencing, we examined the molecular features of breast cancers using 194 patients from Nigeria and 1037 patients from The Cancer Genome Atlas (TCGA). Relative to Black and White cohorts in TCGA, Nigerian HR + /HER2 - tumors are characterized by increased homologous recombination deficiency signature, pervasive TP53 mutations, and greater structural variation-indicating aggressive biology. GATA3 mutations are also more frequent in Nigerians regardless of subtype. Higher proportions of APOBEC-mediated substitutions strongly associate with PIK3CA and CDH1 mutations, which are underrepresented in Nigerians and Blacks. PLK2, KDM6A, and B2M are also identified as previously unreported significantly mutated genes in breast cancer. This dataset provides novel insights into potential molecular mechanisms underlying outcome disparities and lay a foundation for deployment of precision therapeutics in underserved populations.

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.

Forensic odontological observations in the victims of DANA air crash.

INTRODUCTION: Forensic odontology or forensic dentistry is that aspect of forensic science that uses the application of dental science for the identification of unknown human remains and bite marks. Deaths resulting from mass disasters such as plane crash or fire incidence have always been given mass burial in Nigeria. This was obviously due to the fact that Forensic Pathologists whose roles involve disaster victim identification were not available at that time. However, in the DANA air crash in Lagos in 2012, the Forensic pathologist and dental teams were invited for the first time to identify the victims. The objectives of this paper are to identify the extent of victims' identification using Forensic odontology alone and its combination with DNA analysis. It also presents the pattern of fractures seen in the mandible and maxilla of the victims. METHODS: The bodies were dissected using following the standard protocol dissection. Prior to this all the victims had Dental Radiological Examination. The oral cavities were exposed after which the Odontology team was invited for photographing first, followed by dental charting. Fractures of the mandible, maxilla including the anatomical regions were all recorded and photographed. Dental prosthesis, restorations, crowns and bridge and other findings were also noted, recorded and compared with ante mortem records where available. RESULTS: A total of 152 bodies were recovered from the crash site while 148 victims were eventually identified through a combination of DNA analysis and forensic odontology. This represented 97.4%. Forensic odontology was the primary identifier in 10%. There were no fingerprinting information in this country at present therefore, it could not be used. A total of 89 (60%) were males while females accounted for 59(40%). This gives a ratio of 1.5:1. Most of the victims were in the age group 30-49 years; this represented 52% of the victims while the least involved age groups were victims above 60 years of age which accounted for only 4.7%. Mandibular fractures were seen in 29 victims, maxilla in 15, combined mandibullo/maxillary in 15 victims, while 89 victims had no jaw fracture. The most common area of fracture in the mandible was the body which accounted for 36.4%, closely followed by parasymphyseal region 31.9%, symphyseal 22.7% and the angle 9.0%. The most common fracture in the maxillae was palatal split fracture which accounted for 52%, this was followed by pterygoid 24%, alveolar 8% and multiple locations 16%. CONCLUSION: A combination of DNA analysis and forensic odontology was able to identify a total of 148 victims out of 152 representing 97.4%. Forensic odontology was the primary identifier in only 10%. In the latter, poor and lack of dental records were responsible for this very low figure. The most common area of fracture in the mandible was the body which accounted for 36.4%, while that of the maxillae was palatal fracture which accounted for 52%. Padding of the back of the seats in the aircraft should be canvassed for to provide Cushing effect for passengers.

Forensic Investigation of mass disasters in Nigeria: A review.

This paper is to establish the present state of things in the country in terms of legal framework and the availability of personnel with a view to presenting an overview of proper mass disaster investigations. This is a retrospective review of mass disasters in Nigeria that occurred within the last 20 years. The study therefore reviews the state of the forensic investigation of the mass disasters as well as the efforts made to identify the victims of the disaster. The process of proper forensic investigation from the stage of evaluation of the scene and recovery process to the final identification of victims are presented to serve as a protocol for the country. The assessment of the present state of preparedness in Nigeria is also examined with a view to improving the practice to international standards. Data were retrieved from official documents from the aviation industry as well as Nigeria news reports. The standard protocols for disaster victim identification were retrieved from the guide released by the INTERPOL. The state of preparedness of the country and recommendations for improvement are presented. The Federal government and the states of the federation should without further delay put in place the process of reviewing the law of Coroner's system and provide the enabling environment for the proper forensic investigation. The training curriculum of the first responders should incorporate mass disaster investigations in order to produce efficient officers and personnel. A functional disaster victim identification (DVI) team is strongly advocated to incorporate different professionals involved in mass disaster management.