Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Benign breast disease and breast cancer risk in African women: a case-control study.

PURPOSE: To examine the association between benign breast disease (BBD) and breast cancer (BC) in a heterogeneous population of African women. METHODS: BC cases and controls were enrolled in three sub-Saharan African countries, Nigeria, Cameroon, and Uganda, between 1998 and 2018. Multivariable logistic regression was used to test the association between BBD and BC. Risk factors dually associated with BBD and BC were selected. Using a parametric mediation analysis model, we assessed if selected BC risk factors were mediated by BBD. RESULTS: Of 6,274 participants, 55.6% (3,478) were breast cancer cases. 360 (5.7%) self-reported BBD. Fibroadenoma (46.8%) was the most commonly reported BBD. Women with a self-reported history of BBD had greater odds of developing BC than those without (adjusted odds ratio [aOR] 1.47, 95% CI 1.13-1.91). Biopsy-confirmed BBD was associated with BC (aOR 2.25, 95% CI 1.26-4.02). BBD did not significantly mediate the effects of any of the selected BC risk factors. CONCLUSIONS: In this study, BBD was associated with BC and did not significantly mediate the effects of selected BC risk factors.

Unawareness of breast cancer family history among African women.

Introduction: comprehensive cancer risk assessment services are lacking in most sub-Saharan African countries and the use of accurate family history (FH) information could serve as a cheap strategy for risk evaluation. The aim of this study is to determine the proportion of women unaware of family history of cancer among female relatives and associated socio-demographic characteristics. Methods: using case-control data on breast cancer among 4294 women in Nigeria, Uganda and Cameroon, we investigated the proportion of women unaware of family history of cancer among their female relatives. The association between participants' response to their awareness of female relatives' cancer history and socio-demographic characteristics was analysed according to case-control status, family side and distance of relation. Results: the proportion of women unaware if any relative had cancer was 33%, and was significantly higher among controls (43.2%) compared to 23.9% among cases (p<0.001) (Adjusted Odds Ratio (OR) = 2.51, 95% CI = 2.14 - 2.95). Age, education and marital status remained significantly associated with being unaware of FH among controls on multiple regression. Conclusion: about a third of women interviewed did not know about cancer history in at least one of their female relatives. Efforts aimed at improving cancer awareness in sub-Saharan Africa (SSA) are needed. Our findings could be useful for future studies of cancer risk assessment in SSA.

Benign breast disease and breast cancer risk in African women: A case-control study.

Purpose: To examine the association between benign breast disease (BBD) and breast cancer (BC) in a heterogeneous population of African women. Methods: BC cases and matched controls were enrolled in three sub-Saharan African countries, Nigeria Cameroon, and Uganda, between 1998-2018. Multivariable logistic regression was used to test the association between BBD and BC. Risk factors dually associated with BBD and BC were selected. Using a parametric mediation analysis model, we assessed if selected BC risk factors were mediated by BBD. Results: Of 6418 participants, 55.7% (3572) were breast cancer cases. 360 (5.7%) self-reported BBD. Fibroadenoma (46.8%) was the most reported BBD. Women with a self-reported history of BBD had greater odds of developing BC than those without (adjusted odds ratio [aOR] = 1.47, 95% CI: 1.13-1.91). Biopsy-confirmed BBD was associated with BC (aOR = 3.11, 95% CI: 1.78-5.44). BBD did not significantly mediate the effects of any of the selected BC risk factors. Conclusions: In this study, BBD was associated with BC and did not significantly mediate the effects of selected BC risk factors.

Fibrinogen; a predictor of injury severity and mortality among patients with traumatic brain injury in Sub-Saharan Africa: a prospective study.

Introduction: Fibrinogen levels drop quicker than any other factors in severe trauma such as Traumatic Brain Injury (TBI). Contemporaneous studies show that fibrinogen concentrations < 2 g/L are strongly related to mortality. However, little is known regarding fibrinogen levels and TBI severity as well as mortality in sub-Saharan Africa. We therefore set out to determine whether fibrinogen levels are associated with TBI severity and seven days outcomes. Objectives: To determine the sensitivity and specificity of fibrinogen levels and the association with severity and mortality among TBI patients at Mulago Hospital. Methods: We prospectively enrolled 213 patients with TBI aged between 13 and 60 years of age and presenting within 24hrs of injury. Patients with pre-existing coagulopathy, concurrent use of anticoagulant or antiplatelet agents, pre-existing hepatic insufficiency, diabetes mellitus and who were pregnant were excluded. Fibrinogen levels were determined using the Clauss fibrinogen assay. Results: Majority of the patients were male (88.7%) and nearly half were aged 30 or less (48.8%). Fibrinogen levels less than 2g/L were observed in 74 (35.1%) of the patients while levels above 4.5 g/L were observed in 30(14.2%) of the patients. The average time spent in the study was 3.7 ± 2.4 days. The sensitivity and specificity using fibrinogen < 2g/L was 56.5% and 72.9% respectively. Fibrinogen levels predict TBI severity with an AUC = 0.656 (95% CI 0.58-0.73: p = 0.000) Fibrinogen levels < 2g/L (hypofibrinogenemia) were independently associated with severe TBI. (AOR 2.87 CI,1.34-6.14: p = 0.007). Levels above 4.5g/L were also independently associated with injury severity (AOR 2.89, CI 1.12-7.48: p < 0.05) Fibrinogen levels more than 4.5g/L were independently associated with mortality (OR 4.5, CI;1.47-13.61, p < 0.05). Conclusions: The fibrinogen level is a useful tool in predicting severity including mortality of TBI in our settings. We recommend the routine use of fibrinogen levels in TBI patient evaluations as levels below 2g/L and levels above 4.5g/L are associated with severe injuries and mortality.

Validation of the Nigerian Breast Cancer Study Model for Predicting Individual Breast Cancer Risk in Cameroon and Uganda.

BACKGROUND: The Nigerian Breast Cancer Study (NBCS) model is a new risk assessment tool developed for predicting risk of invasive breast cancer in Nigeria. Its applicability outside of Nigeria remains uncertain as it has not been validated in other sub-Saharan Africa populations. METHODS: We conducted a case-control study among women with breast cancer and controls ascertained in Cameroon and Uganda from 2011 to 2016. Structured questionnaire interviews were performed to collect risk factor characteristics. The NBCS model, the Gail model, the Gail model for Black population, and the Black Women's Health Study model were applied to the Cameroon and Uganda samples separately. Nigerian as well as local incidence rates were incorporated into the models. Receiver-Operating Characteristic analyses were performed to indicate discriminating capacity. RESULTS: The study included 550 cases (mean age 46.8 ± 11.9) and 509 controls (mean age 46.3 ± 11.7). Compared with the other three models, the NBCS model performed best in both countries. The discriminating accuracy of the NBCS model in Cameroon (age-adjusted C-index = 0.602; 95% CI, 0.542-0.661) was better than in Uganda (age-adjusted C-index = 0.531; 95% CI, 0.459-0.603). CONCLUSIONS: These findings demonstrate the potential clinical utility of the NBCS model for risk assessment in Cameroon. All currently available models performed poorly in Uganda, which suggests that the NBCS model may need further calibration before use in other regions of Africa. IMPACT: Differences in risk profiles across the African diaspora underscores the need for larger studies and may require development of region-specific risk assessment tools for breast cancer.

Comparison of the PIPAS severity score tool and the QSOFA criteria for predicting in-hospital mortality of peritonitis in a tertiary hospital in Uganda: a prospective cohort study.

BACKGROUND: The majority of the prognostic scoring tools for peritonitis are impractical in low resource settings because they are complex while others are quite costly. The quick Sepsis-related Organ Failure Assessment (qSOFA) score and the Physiologic Indicators for Prognosis in Abdominal Sepsis (PIPAS) severity score are two strictly bedside prognostic tools but their predictive ability for mortality of peritonitis is yet to be compared. We compared the predictive ability of the qSOFA criteria and the PIPAS severity score for in-hospital mortality of peritonitis. METHOD: This was a prospective cohort study on consecutive peritonitis cases managed surgically in a tertiary hospital in Uganda between October 2020 to June 2021. PIPAS severity score and qSOFA score were assessed preoperatively for each case and all cases were then followed up intra- and postoperatively until discharge from the hospital, or up to 30 days if the in-hospital stay was prolonged; the outcome of interest was in-hospital mortality. We used Receiver Operating Characteristic curve analysis to assess and compare the predictive abilities of these two tools for peritonitis in-hospital mortality. All tests were 2 sided (p < 0.05) with 95% confidence intervals. RESULTS: We evaluated 136 peritonitis cases. Their mean age was 34.4 years (standard deviation = 14.5). The male to female ratio was 3:1. The overall in-hospital mortality rate for peritonitis was 12.5%. The PIPAS severity score had a significantly better discriminative ability (AUC = 0.893, 95% CI 0.801-0.986) than the qSOFA score (AUC = 0.770, 95% CI 0.620-0.920) for peritonitis mortality (p = 0.0443). The best PIPAS severity cut-off score (a score of > = 2) had sensitivity and specificity of 76.5%, and 93.3% respectively, while the corresponding values for the qSOFA criteria (score > = 2), were 58.8% and 98.3% respectively. CONCLUSIONS: The in-hospital mortality in this cohort of peritonitis cases was high. The PIPAS severity score tool has a superior predictive ability and higher sensitivity for peritonitis in-hospital mortality than the qSOFA score tool although the latter tool is more specific. We recommend the use of the PIPAS severity score as the initial prognostic tool for peritonitis cases in the emergency department.

Quality of life of adult individuals with intestinal stomas in Uganda: a cross sectional study.

INTRODUCTION: Intestinal stomas remain important life-saving surgical options in a wide range of gastrointestinal pathologies globally. Living with a stoma has potential to impair the patient's quality of life, often with associated negative psychological effects. OBJECTIVE: To evaluate the quality of life among intestinal stoma patients under Mulago National Referral Hospital (MNRH), with emphasis on psychological effects and effects on family-social interactions. METHODOLOGY: A cross-sectional study carried out at surgical outpatient clinics of MNRH between January and June 2018. Data was collected using Stoma-QOL questionnaire, PHQ-9 and GAD-7 from 51 participants who had lived with intestinal stomas for at least a month. RESULTS: Of the 51 participants, male: female ratio was 4:1 and aged 18-84 years (mean age 44.04+18.47 years). 76.5% had colostomy; 23.5% had ileostomy. Majority (88.2%) had temporary stomas. The overall mean Stoma-QOL score was 55.12+ 17.04. Only about a quarter (24%) of participants had Stoma-QOL scores >70 (best). Most patients exhibited negative psychological effects (anxiety-100%, concerns about changed body image - 96.1% and depression - 88.4%). CONCLUSION: Most participants had low levels of stoma-related quality of life, suffered negative psychological effects and exhibited limited social interactions. This calls for efforts to support Stoma patients adapt beter life.

Prevalence and Predictors of Cancellation of Elective Surgical Procedures at a Tertiary Hospital in Uganda: A Cross-Sectional Study.

Introduction. The cancellation of elective procedures has been shown to waste resources and to have the potential to increase morbidity and mortality among patients. This study aimed to determine the prevalence of the cancellation of elective surgical procedures and to identify the factors associated with these cancellations at Mulago Hospital, a large public hospital in Kampala, Uganda. METHODS: A cross-sectional study was conducted from January 10, 2018, to February 20, 2018. We recruited patients of all ages who were admitted to surgical wards and scheduled for elective surgery. Data on patients' demographic characteristics and diagnosis, as well as the specialty of the surgery, the planned procedure, the specific operating theatre, cancellation, and the reasons for cancellation were extracted and analyzed using logistic regression. RESULTS: Of a total of 400 cases, 115 procedures were canceled-a cancellation prevalence of 28.8%. Orthopedic surgery had the highest cancellation rate, at 40.9% (n = 47). Facility-related factors were responsible for 67.8% of all cancellations. The most common reason for cancellation was insufficient time in the theatre to complete the procedure on the scheduled day. No procedures were canceled because of a lack of intensive care unit beds. There was a significant association between surgical specialty and cancellation (P < 0.05) at multivariate analysis. CONCLUSION: The prevalence of cancellation of elective surgical procedures at Mulago Hospital was 28.8%, with orthopedic surgery having the highest cancellation rate. Two-thirds of the factors causing cancellations were facility-related, and more than 50% of all cancellations were potentially preventable. Quality-improvement strategies are necessary in the specialties that are susceptible to procedure cancellation because of facility factors.

Prevalence of Inherited Mutations in Breast Cancer Predisposition Genes among Women in Uganda and Cameroon.

BACKGROUND: Sub-Saharan Africa (SSA) has a high proportion of premenopausal hormone receptor negative breast cancer. Previous studies reported a strikingly high prevalence of germline mutations in BRCA1 and BRCA2 among Nigerian patients with breast cancer. It is unknown if this exists in other SSA countries. METHODS: Breast cancer cases, unselected for age at diagnosis and family history, were recruited from tertiary hospitals in Kampala, Uganda and Yaoundé, Cameroon. Controls were women without breast cancer recruited from the same hospitals and age-matched to cases. A multigene sequencing panel was used to test for germline mutations. RESULTS: There were 196 cases and 185 controls with a mean age of 46.2 and 46.6 years for cases and controls, respectively. Among cases, 15.8% carried a pathogenic or likely pathogenic mutation in a breast cancer susceptibility gene: 5.6% in BRCA1, 5.6% in BRCA2, 1.5% in ATM, 1% in PALB2, 0.5% in BARD1, 0.5% in CDH1, and 0.5% in TP53. Among controls, 1.6% carried a mutation in one of these genes. Cases were 11-fold more likely to carry a mutation compared with controls (OR = 11.34; 95% confidence interval, 3.44-59.06; P < 0.001). The mean age of cases with BRCA1 mutations was 38.3 years compared with 46.7 years among other cases without such mutations (P = 0.03). CONCLUSIONS: Our findings replicate the earlier report of a high proportion of mutations in BRCA1/2 among patients with symptomatic breast cancer in SSA. IMPACT: Given the high burden of inherited breast cancer in SSA countries, genetic risk assessment could be integrated into national cancer control plans.

The clinical presentation and early outcomes of necrotizing fasciitis in a Ugandan Tertiary Hospital--a prospective study.

BACKGROUND: Necrotizing fasciitis is an infectious process characterized by rapidly progressing necrosis of superficial fascia and subcutaneous tissue with subsequent necrosis of overlying skin.Necrotizing fasciitis is a rare but fatal infection. The worldwide incidence is at 0.4 per 100,000. Mortality is up to 80% with no intervention, and 30-50% with intervention. Delay in intervention is associated with poor outcome. The risk factors for necrotizing fasciitis are diabetes mellitus, HIV, malignancy, illicit drug use, malnutrition among others.The aim of this study was to describe the clinical presentation and early outcomes of necrotizing fasciitis amongst Ugandan patients. METHODS: A prospective descriptive case series study conducted at Mulago National Referral and Teaching hospital from 5th January to 30th April 2011. Patients with necrotizing fasciitis were consecutively recruited after clinical evaluation, laboratory and microbiological tests were performed. Aggressive debridement was done and broad-spectrum antibiotics administered. Patients were followed up on surgical wards. Ethical approval was obtained. RESULTS: Thirty five patients were recruited over a 4 months period. More males were affected with, M: F 3:1. The 20-40 years age group was most affected. Attainment of healthy granulation tissue took 19 days on average. Mortality rate was 14% (5/35). Limbs were the most affected body parts 20/35 (57%), the scrotum and perineum (23%). Among infants the scalp was the most affected. Co-morbidities included HIV 8/35 (17%), and DM (5%) among others. The commonest organisms were gram negative. Split skin grafting was necessary in 74% (26/35) of patients. CONCLUSION: There were a high number of patients with necrotizing fasciitis; it was associated with low mortality but high morbidity (long hospital stay). There was a high preponderance to males and limbs were the more affected body parts.