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.

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.

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.

Conjunctival melanoma in Southwestern Nigeria: a case series and review of literature.

PURPOSE: Conjunctival melanoma is a rare tumor worldwide and is extremely rare among black population. This study aims to report the demographics, clinical presentation, treatment, and outcome of patients seen in an indigenous black population in Southwestern Nigeria. METHODS: All patients histologically diagnosed with conjunctival melanoma and managed in the facility were reviewed. Their demographics, clinical presentation, treatment received, outcome of treatment, and histopathological features were analyzed. RESULTS: Six patients (males = 2) with a mean age of 49.8 years were managed over 11 years (range 25-75 years). The right eye was involved in three patients, while one patient had bilateral non-simultaneous tumor. All six patients presented with pigmented growth over the ocular surface of varying duration, confirmed as malignant melanoma at histopathology after an excision biopsy (two patients), incision biopsy (one patient), or orbital exenteration (three patients). One patient who had complete adjuvant treatment postoperatively remained alive and tumor-free at 7-year follow-up, one patient is presently on chemotherapy, one patient died while on admission, and the remaining three patients abandoned further postoperative treatment and defaulted from follow-up. CONCLUSION: Conjunctival melanoma is a rare ocular malignancy in Southwestern Nigeria, and patients present with advanced disease with potential poor outcome.

Microsatellite Instability Is Common in Colorectal Cancer in Native Nigerians.

BACKGROUND: Colorectal cancer (CRC) is the fifth most common cancer in Africa, with significant differences in incidence, biology and clinical behavior from other populations. MATERIALS AND METHODS: We studied prevalence and clinicopathological features of microsatellite instability (MSI) and young onset CRC in 83 archival samples from the University of Ibadan, Nigeria. RESULTS: Nigerian cases of CRC were MSI-high in 43% and MSI-high CRC had significantly lower histological heterogeneity than microsatellite-stable CRC (20% vs. 55% respectively, p=0.046). Presence of signet ring cell differentiation (10-50% of tumor) was significantly higher in younger patients with CRC (<50 years) (odds ratio(OR)=5.93, 95% confidence interval(CI)=1.17-29.95, p=0.038). Poor differentiation (34%), invasive growth (96%), and high prevalence of mucinous (10%) and signet ring cell adenocarcinomas (4%) were among distinct features of Nigerian patients with CRC. CONCLUSION: MSI-high CRC is more common in West Africa and more detailed molecular and genetic analysis is warranted as CRC incidence and mortality continue to increase in the Sub-Saharan Africa.

The clinical effectiveness of fine needle aspiration biopsy in patients with palpable breast lesions seen at the University College Hospital, Ibadan, Nigeria: A 10-year retrospective study.

BACKGROUND: Although open surgical biopsy is the 'gold standard' for diagnosis of palpable breast lesions, in recent years two types of minimally invasive breast biopsy techniques, core needle biopsy and fine needle aspiration biopsy (FNAB), have become established for the diagnostic evaluation of palpable breast lesions. AIMS: This study was undertaken to evaluate the clinical effectiveness of FNAB as a first line diagnostic procedure in the management of patients with breast lumps in University College Hospital (UCH), Ibadan, using the suggested thresholds for cytology performance as recommended by the United Kingdom National Health Services Breast Screening Programme (NHSBSP). SETTINGS AND DESIGN: A 10-year retrospective cohort study carried out in the Pathology Department of UCH. MATERIALS AND METHODS: All FNAB and histologically diagnosed cases of breast lesions in the pathology department between January 1996 and December 2005 were reviewed. The cytological diagnoses were then categorized into one of five diagnostic categories in accordance with the recommendations of the NHSBSP. RESULTS: The positive predictive value for malignancy was 99.3% with a complete sensitivity of 97.7% and specificity (full) of 94.2%. CONCLUSIONS: The high quality assurance measures obtained in this study affirms FNAB as a clinically effective diagnostic procedure for breast lesions.

Lymphomas in sub-Saharan Africa--what can we learn and how can we help in improving diagnosis, managing patients and fostering translational research?

Approximately 30 000 cases of non-Hodgkin lymphoma (NHL) occur in the equatorial belt of Africa each year. Apart from the fact that Burkitt lymphoma (BL) is very common among children and adolescents in Africa and that an epidemic of human immunodeficiency virus (HIV) infection is currently ongoing in this part of the world, very little is known about lymphomas in Africa. This review provides information regarding the current infrastructure for diagnostics in sub-Saharan Africa. The results on the diagnostic accuracy and on the distribution of different lymphoma subsets in sub-Saharan Africa were based on a review undertaken by a team of lymphoma experts on 159 fine needle aspirate samples and 467 histological samples during their visit to selected sub-Saharan African centres is presented. Among children (<18 years of age), BL accounted for 82% of all NHL, and among adults, diffuse large B-cell lymphoma accounted for 55% of all NHLs. Among adults, various lymphomas other than BL, including T-cell lymphomas, were encountered. The review also discusses the current strategies of the International Network of Cancer Treatment and Research on improving the diagnostic standards and management of lymphoma patients and in acquiring reliable clinical and pathology data in sub-Saharan Africa for fostering high-quality translational research.

Prevalence of Helicobacter pylori among Nigerian patients with dyspepsia in Ibadan.

INTRODUCTION: Determination of the true prevalence of Helicobacter pylori (H. pylori) is difficult in a hyper-endemic area like Nigeria with use of serological tests because of their low discriminatory power between previous and current infections. The use of biopsy based methods will go a long way to mitigate this problem. We investigated the prevalence of H. pylori in dyspeptic patients and its relationship with gastroduodenal pathologies using gastric biopsy histology and rapid urease test. METHODS: Eighty-six consecutive adult patients with dyspepsia underwent upper gastrointestinal endoscopy using forward-viewing endoscopes. Antral biopsy specimens were collected for histology and rapid urease test. Diagnosis of H. pylori infection was made if both or either of the tests was positive. RESULTS: Of the 86 subjects, there were 39 (45.3%) males and 47 (54.7%) females. The age range was 23 to 85 years with a mean of 49.19±13.75 years. Diagnosis of H. pylori was made in 55 (64%) patients. Gastritis was the commonest endoscopic finding (60.5%), serious gastroduodenal pathology (gastric ulcer, duodenal ulcer and gastric cancer) were documented in only 12 (14%) patients. Thirty three (63.5%) of the 55 patients with gastritis had H. pylori infection while 7 (58.3%) of the 12 patients with serious gastroduodenal lesions had the infection. Thirteen (72.2%) of the 18 patients that had normal endoscopic findings were H. pylori positive. CONCLUSION: The prevalence of H. pylori among dyspeptics using biopsy based methods is high in the South-Western part of Nigeria. It is therefore important to test and treat H. pylori among Nigerians with dyspepsia.

Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer.

PURPOSE: Compared with white women, black women experience a disproportionate burden of aggressive breast cancer for reasons that remain unknown and understudied. In the first study of its kind, we determined the distribution of molecular subtypes of invasive breast tumors in indigenous black women in West Africa. PATIENTS AND METHODS: The study comprised 507 patients diagnosed with breast cancer between 1996 and 2007 at six geographic regions in Nigeria and Senegal. Formalin-fixed and paraffin-embedded sections were constructed into tissue microarrays and immunostained with 15 antibodies. Five molecular subtypes were determined, and hierarchical cluster analysis was conducted to explore subgroups for unclassified cases. RESULTS: The mean (+/- standard deviation) age of 378 patients in the first cohort was 44.8 +/- 11.8 years, with the majority of women presenting with large (4.4 +/- 2.0 cm) high-grade tumors (83%) in advanced stages (72% node positive). The proportions of estrogen receptor (ER) -positive, progesterone receptor-positive, and human epidermal growth factor receptor 2 (HER2) -positive tumors were 24%, 20%, and 17%, respectively. Triple negativity for these markers was predominant, including basal-like (27%) and unclassified subtype (28%). Other subtypes were luminal A (27%), luminal B (2%), and HER2 positive/ER negative (15%). The findings were replicated in the second cohort of 129 patients. The unclassified cases could be grouped into a bad prognosis branch, with expression of vascular endothelial growth factor, B-cell lymphoma extra-large protein, and Cyclin E, and a good prognosis branch, with expression of B-cell lymphoma protein 2 and Cyclin D1. CONCLUSION: These findings underscore the urgent need for research into the etiology and treatment of the aggressive molecular subtypes that disproportionately affect young women in the African diaspora.

Visual impairment from fibrous dysplasia in a middle-aged African man: a case report.

INTRODUCTION: Fibrous dysplasia is a benign tumour of the bones and is a disease of unknown aetiology. This report discusses a case of proptosis and visual deterioration with associated bony mass involving the right orbit. CASE PRESENTATION: A 32-year-old Nigerian man of Yoruba ethnic origin presented to the eye clinic of our hospital with right-eye proptosis and visual deterioration of 7-year duration. Presentation was preceded by a history of trauma. Proptosis was preceded by trauma but was non-pulsatile with no thrill or bruit but was associated with bony orbital mass. The patient reported no weight loss. Examination of his right eye showed visual acuity of 6/60 with relative afferent pupillary defect. Fundal examination revealed optic atrophy. Computed tomography showed an expansile bony mass involving all the walls of the orbit. The bony orbital mass was diagnosed histologically as fibrous dysplasia. Treatment included orbital exploration and orbital shaping to create room for the globe and relieve pressure on the optic nerve. CONCLUSION: Fibrous dysplasia should be considered in the differential diagnosis of slowly developing proptosis with associated visual loss in young adults.

The autopsy: knowledge, attitude, and perceptions of doctors and relatives of the deceased.

CONTEXT: Despite the crucial role that autopsy plays in the development of the science and practice of medicine, autopsy rates have been declining throughout the world in recent decades. OBJECTIVE: To identify factors influencing the acceptance of autopsies in Nigeria. DESIGN: Cross-sectional survey of the knowledge, attitude, and perceptions of doctors and relatives of deceased patients on factors influencing acceptance of autopsy at the University College Hospital, Ibadan, Nigeria. RESULTS: Only 38% of relatives had satisfactory knowledge about autopsy and about 50% of doctors knew that physicians' desire for autopsy should not override patients' consent. Doctors identified difficulty in obtaining consent from relatives of deceased patients, administrative problems in requesting autopsy, and delay in obtaining autopsy report as major reasons responsible for the decline in autopsy requests, whereas relatives of the deceased cited fear of mutilation, concerns about delaying the funeral, and objection by the patient before death as reasons for refusal to grant permission for an autopsy. Sociodemographic factors such as age, occupation, religion, ethnicity, and level of education significantly influenced willingness to give consent for autopsy. CONCLUSIONS: There is need for concerted effort on the part of clinicians, pathologists, the public, and the government to resuscitate and sustain the practice of autopsy in Nigeria.

Sinonasal paraganglioma: a case report.

OBJECTIVE: To highlight the importance of a high index of suspicion and meticulous evaluation of a patient with bleeding sinonasal mass in the diagnosis of sinonasal paraganglioma. METHOD: Case report of a 39-year-old female who presented with a bleeding lobulated left nasal mass necessitating multiple blood transfusions is presented. RESULT: Diagnostic investigations revealed that the patient was HIV-positive (ELISA and Western blot) and a tumour histology of paraganglioma. She had a CD4+ count of 487 cells/mm3. The urinary vanillylmandelic acid assay and echocardiography were normal. Subsequently, she had complete tumour excision through a medial maxillectomy and has remained without a recurrence 12 months after. CONCLUSION: To our knowledge, this is the first report in the world literature of sinonasal paraganglioma in a HIV-positive patient and the first reported case of sinonasal paraganglioma in Africa. It is, however, not clear from this report if the patient's HIV status preceded her development of the paraganglioma or not.

Liver dysfunction in steady state sickle cell disease.

The liver is one of the organs involved in the multiorgan failure that occurs in sickle cell disease, the pathophysiology of liver disease in this condition is complex because of the interrelated multifactorial causes. Liver dysfunction was assessed in both paediatric and adult sickle cell disease patients in the steady state. The transaminases and alkaline phosphatase were analysed by automation while coagulation studies were done manually. The mean (range) of Alanine transaminase (ALT), Aspartate transaminase (AST) and alkaline phosphatase (ALP) were 23.0 (2-77) IU, 48.5 (15-120) IU, 227.5 (37-1200) IU respectively. ALT and AST levels were less than 100 IU in over 95% of the patients. The gender or age of the patients did not significantly affect the level of these three enzymes. There was close association between the liver size and elevation of the liver enzymes except for alkaline phosphatase (ALT=.017, AST=.009, ALP=.056). Twenty-five percent of the patients had normal enzymes while 13% had derangement of the three enzymes, 19%, 50% and 74% had abnormal ALT, AST and ALP respectively. Only 22% and 5% had deranged PT and APTT respectively. In conclusion minimal elevation of the tramsaminases which is not gender or age dependent were observed in steady state sickle cell disease, higher levels of alkaline phosphatase may be due to associated vasoocclussive crises involving the bones rather than a pathology of the liver.