Heterogeneous genetic architectures of prostate cancer susceptibility in sub-Saharan Africa.

Men of African descent have the highest prostate cancer incidence and mortality rates, yet the genetic basis of prostate cancer in African men has been understudied. We used genomic data from 3,963 cases and 3,509 controls from Ghana, Nigeria, Senegal, South Africa and Uganda to infer ancestry-specific genetic architectures and fine-map disease associations. Fifteen independent associations at 8q24.21, 6q22.1 and 11q13.3 reached genome-wide significance, including four new associations. Intriguingly, multiple lead associations are private alleles, a pattern arising from recent mutations and the out-of-Africa bottleneck. These African-specific alleles contribute to haplotypes with odds ratios above 2.4. We found that the genetic architecture of prostate cancer differs across Africa, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that African prostate cancer associations are largely governed by neutral evolution. Collectively, our findings emphasize the utility of conducting genetic studies that use diverse populations.

Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men.

Androgenetic alopecia is a highly heritable trait. However, much of our understanding about the genetics of male pattern baldness comes from individuals of European descent. Here, we examined a novel dataset comprising 2,136 men from Ghana, Nigeria, Senegal, and South Africa that were genotyped using a custom array. We first tested how genetic predictions of baldness generalize from Europe to Africa, finding that polygenic scores from European GWAS yielded AUC statistics that ranged from 0.513 to 0.546, indicating that genetic predictions of baldness in African populations performed notably worse than in European populations. Subsequently, we conducted the first African GWAS of androgenetic alopecia, focusing on self-reported baldness patterns at age 45. After correcting for present age, population structure, and study site, we identified 266 moderately significant associations, 51 of which were independent (p-value < 10-5, r2 < 0.2). Most baldness associations were autosomal, and the X chromosomes does not appear to have a large impact on baldness in African men. Finally, we examined the evolutionary causes of continental differences in genetic architecture. Although Neanderthal alleles have previously been associated with skin and hair phenotypes, we did not find evidence that European-ascertained baldness hits were enriched for signatures of ancient introgression. Most loci that are associated with androgenetic alopecia are evolving neutrally. However, multiple baldness-associated SNPs near the EDA2R and AR genes have large allele frequency differences between continents. Collectively, our findings illustrate how evolutionary history contributes to the limited portability of genetic predictions across ancestries.

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

Drivers of disparities in stage at diagnosis among women with breast cancer: South African breast cancers and HIV outcomes cohort.

OBJECTIVE: In low- and middle-income countries (LMICs), advanced-stage diagnosis of breast cancer (BC) is common, and this contributes to poor survival. Understanding the determinants of the stage at diagnosis will aid in designing interventions to downstage disease and improve survival from BC in LMICs. METHODS: Within the South African Breast Cancers and HIV Outcomes (SABCHO) cohort, we examined factors affecting the stage at diagnosis of histologically confirmed invasive breast cancer at five tertiary hospitals in South Africa (SA). The stage was assessed clinically. To examine the associations of the modifiable health system, socio-economic/household and non-modifiable individual factors, hierarchical multivariable logistic regression with odds of late-stage at diagnosis (stage III-IV), was used. RESULTS: The majority (59%) of the included 3497 women were diagnosed with late-stage BC disease. The effect of health system-level factors on late-stage BC diagnosis was consistent and significant even when adjusted for both socio-economic- and individual-level factors. Women diagnosed in a tertiary hospital that predominantly serves a rural population were 3 times (OR = 2.89 (95% CI: 1.40-5.97) as likely to be associated with late-stage BC diagnosis when compared to those diagnosed at a hospital that predominantly serves an urban population. Taking more than 3 months from identifying the BC problem to the first health system entry (OR = 1.66 (95% CI: 1.38-2.00)), and having luminal B (OR = 1.49 (95% CI: 1.19-1.87)) or HER2-enriched (OR = 1.64 (95% CI: 1.16-2.32)) molecular subtype as compared to luminal A, were associated with a late-stage diagnosis. Whilst having a higher socio-economic level (a wealth index of 5) reduced the probability of late-stage BC at diagnosis, (OR = 0.64 (95% CI: 0.47-0.85)). CONCLUSION: Advanced-stage diagnosis of BC among women in SA who access health services through the public health system was associated with both modifiable health system-level factors and non-modifiable individual-level factors. These may be considered as elements in interventions to reduce the time to diagnosis of breast cancer in women.

Testing the generalizability of ancestry-specific polygenic risk scores to predict prostate cancer in sub-Saharan Africa.

BACKGROUND: Genome-wide association studies do not always replicate well across populations, limiting the generalizability of polygenic risk scores (PRS). Despite higher incidence and mortality rates of prostate cancer in men of African descent, much of what is known about cancer genetics comes from populations of European descent. To understand how well genetic predictions perform in different populations, we evaluated test characteristics of PRS from three previous studies using data from the UK Biobank and a novel dataset of 1298 prostate cancer cases and 1333 controls from Ghana, Nigeria, Senegal, and South Africa. RESULTS: Allele frequency differences cause predicted risks of prostate cancer to vary across populations. However, natural selection is not the primary driver of these differences. Comparing continental datasets, we find that polygenic predictions of case vs. control status are more effective for European individuals (AUC 0.608-0.707, OR 2.37-5.71) than for African individuals (AUC 0.502-0.585, OR 0.95-2.01). Furthermore, PRS that leverage information from African Americans yield modest AUC and odds ratio improvements for sub-Saharan African individuals. These improvements were larger for West Africans than for South Africans. Finally, we find that existing PRS are largely unable to predict whether African individuals develop aggressive forms of prostate cancer, as specified by higher tumor stages or Gleason scores. CONCLUSIONS: Genetic predictions of prostate cancer perform poorly if the study sample does not match the ancestry of the original GWAS. PRS built from European GWAS may be inadequate for application in non-European populations and perpetuate existing health disparities.

Skin cancer risk factors among Black South Africans-The Johannesburg Cancer Study, 1995-2016.

BACKGROUND: The Black population has lower skin cancer incidence compared to White, Indian/Asian, and Mixed-race populations in South Africa; however, skin cancer still exists in the Black population. The aim of this study is to identify risk factors associated with skin cancer among Black South Africans. MATERIALS AND METHODS: A case-control study was conducted. Cases were patients with keratinocyte cancers (KCs) and/or melanoma skin cancers (MSCs) and controls were cardiovascular patients. Sociodemographic exposures, environmental health variables, smoking, and HIV status were assessed. Stepwise logistic regression was used to identify risk factors associated with KCs and MSCs. RESULTS: The KCs histological subtypes showed that there were more squamous cell carcinomas (SCCs) (78/160 in females, and 72/160 in males) than basal cell carcinomas (BCCs). The SCC lesions were mostly found on the skin of the head and neck in males (51%, 38/72) and on the trunk in females (46%, 36/78). MSC was shown to affect the skin of the lower limbs in both males (68%, 27/40) and females (59%, 36/61). Using females as a reference group, when age, current place of residency, type of cooking fuel used, smoking, and HIV status were adjusted for, males had an odds ratio (OR) of 2.04 for developing KCs (confidence interval [CI]: 1.08-3.84, p = .028). Similarly, when age, current place of residency, and place of cooking (indoors or outdoors) were adjusted for, males had an OR of 2.26 for developing MSC (CI: 1.19-4.29, p = .012). CONCLUSIONS: Differences in the anatomical distribution of KCs by sex suggest different risk factors between sexes. There is a positive association between being male, smoking, rural dwelling, and a positive HIV status with KCs and being male and rural dwelling with MSC. The rural dwelling was a newly found association with skin cancer and warrants further investigation.

Processing and Analysis of Tissue Samples from Esophageal Cancer Patients in an African Setting.

Although infectious diseases continue to present a major health care problem in Africa, the incidence of cancer is increasing rapidly on the African continent and this merits an increased investment in cancer research in low to medium resource settings. Esophageal squamous cell carcinoma (ESCC) has a high incidence in Eastern and Southern Africa, with late clinical presentation and a very poor prognosis. There is limited research on the molecular pathology of this cancer in Africa, partly as a result of a lack of infrastructure for biobanking and sample processing in many African countries. The aim of this study was to establish a practical and robust workflow to collect, store, and process esophageal cancer samples such that both the tissue architecture and quality of the samples would be preserved and suitable for future genomic research. We developed a workflow that allows storage of fresh biopsy tissue in sterile Eppendorf tubes containing RNAlater, an efficient RNAse inhibitor. We collected 142 ESCC biopsy samples and showed that storage in RNAlater for up to 18 months did not alter tissue morphology, thus allowing histologic assessment by experienced pathologists and determination of tumor content in each biopsied sample. DNA and RNA extracted from tissue samples was assessed for purity, molecular size, and yield. The quantity and quality of nucleic acids obtained were suitable for genomic applications, and whole-exome sequencing of DNA from tumor tissues produced sequence data with a high proportion of both usable reads and correct base calling. We conclude that this workflow may be applicable to a wide range of malignancies for future genomic research in low-resource settings.

Consensus study on the health system and patient-related barriers for lung cancer management in South Africa.

BACKGROUND: Lung cancer is the highest incident cancer globally and is associated with significant morbidity and mortality particularly if identified at a late stage. Poor patient outcomes in low- and middle-income countries (LMIC's) might reflect contextual patient and health system constraints at multiple levels, that act as barriers to prevention, disease recognition, diagnosis, and treatment. Lung cancer screening, even for high-risk patients, is not available in the public health sector in South Africa (SA), where the current HIV and tuberculosis (TB) epidemics often take precedence. Yet, there has been no formal assessment of the individual and health-system related barriers that may delay patients with lung cancer from seeking and accessing help within the public health care system and receiving the appropriate and effective diagnosis and treatment. This study aimed to derive consensus from health-system stakeholders in the urban Gauteng Province of SA on the most important challenges faced by the health services and patients in achieving optimum lung cancer management and to identify potential solutions. METHODS: The study was undertaken among 27 participant stakeholders representing clinical managers, clinicians, opinion leaders from the public health sector and non-governmental organisation (NGO) representatives. The study compromised two components: consensus and engagement. For the consensus component, the Delphi Technique was employed with open-ended questions and item ranking from five rounds of consensus-seeking, to achieve collective agreement on the most important challenges faced by patients and the health services in achieving optimal lung cancer management. For the engagement component, the Nominal Group Technique was used to articulate ideas and reach an agreement on the group's recommendations for solution strategies and approaches. RESULTS: Public health sector stakeholders suggested that a lack of knowledge and awareness of lung cancer, and the apparent stigma associated with the disease and its risk factors, as well as symptoms and signs, are critical to treatment delay. Furthermore, delays in up-referral of patients with suspected lung cancer from district health care level were attributed to inadequate knowledge arising from a lack of in-service training of nurses and doctors regarding oncologic symptoms, risk factors, need for further investigation, interpretation of x-rays and available treatments. At a tertiary level, participants suggested that insufficient availability of specialised diagnostic resources (imaging, cytological and pathological services including biomolecular assessment of lung cancer), theatres, cardiothoracic surgeons, and appropriate therapeutic modalities (chemotherapeutic agents and radiation oncology) are the main barriers to the provision of optimal care. It was suggested that a primary prevention programme initiated by the government that involves private-public partnerships may improve lung cancer management nationally. CONCLUSIONS: Considerable barriers to the early identification and treatment of lung cancer exist. Finding solutions to overcome both individual and health-system level obstacles to lung cancer screening and management are vital to facilitate early identification and treatment, and to improve survival. Furthermore, research on inexpensive biomarkers for asymptomatic disease detection, the introduction of diagnostic imaging tools that utilise artificial intelligence to compensate for inadequate human resources and improving clinical integration across all levels of the healthcare system are essential.

Completeness of Reporting for Breast Cancer Data in the National Pathology-Based Cancer Registry in South Africa.

BACKGROUND: It is important for a cancer registry to have adequate coverage of the catchment area to accurately estimate the cancer burden. This study aimed to determine the pathology-based South African National Cancer Registry's (NCR's) catchment rate of breast cancer cases using a hospital-based cancer registry as reference. METHODS: Using 2 record linkage approaches, a combination of deterministic record linkage (DRL) and probabilistic record linkage (PRL), we linked a breast cancer hospital registry (n = 398) from 2015 with breast cancer registry data from the NCR (n = 16,642). Firstly, using DRL, we matched and linked records using the unique laboratory report number. Records that were not matched using DRL were linked using PRL. Manual reviews of both data sources were then performed to evaluate records that did not match using either DRL or PRL. The NCR's catchment rate was calculated using the total number of matched records from the hospital registry to the NCR breast cancer registry. RESULTS: Of 398 records from the hospital registry, 397 were matched to the NCR breast cancer registry, giving the NCR a catchment rate of 99.75%. A total of 291 records were matched with NCR records by DRL; 95, by PRL; and 11, by manual review. Only 1 record did not match. CONCLUSION: Nearly all hospital breast cancer cases were found in the NCR database. This suggests that the workflow used by the NCR for the identification, collection, and registration of breast cancer cases diagnosed histologically is adequate for this hospital.

A Custom Genotyping Array Reveals Population-Level Heterogeneity for the Genetic Risks of Prostate Cancer and Other Cancers in Africa.

Although prostate cancer is the leading cause of cancer mortality for African men, the vast majority of known disease associations have been detected in European study cohorts. Furthermore, most genome-wide association studies have used genotyping arrays that are hindered by SNP ascertainment bias. To overcome these disparities in genomic medicine, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a genotyping array that is optimized for African populations. The MADCaP Array contains more than 1.5 million markers and an imputation backbone that successfully tags over 94% of common genetic variants in African populations. This array also has a high density of markers in genomic regions associated with cancer susceptibility, including 8q24. We assessed the effectiveness of the MADCaP Array by genotyping 399 prostate cancer cases and 403 controls from seven urban study sites in sub-Saharan Africa. Samples from Ghana and Nigeria clustered together, whereas samples from Senegal and South Africa yielded distinct ancestry clusters. Using the MADCaP array, we identified cancer-associated loci that have large allele frequency differences across African populations. Polygenic risk scores for prostate cancer were higher in Nigeria than in Senegal. In summary, individual and population-level differences in prostate cancer risk were revealed using a novel genotyping array. SIGNIFICANCE: This study presents an Africa-specific genotyping array, which enables investigators to identify novel disease associations and to fine-map genetic loci that are associated with prostate and other cancers.

The multimorbidity profile of South African women newly diagnosed with breast cancer.

Multimorbidity in women with breast cancer may delay presentation, affect treatment decisions and outcomes. We described the multimorbidity profile of women with breast cancer, its determinants, associations with stage at diagnosis and treatments received. We collected self-reported data on five chronic conditions (hypertension, diabetes, cerebrovascular diseases, asthma/chronic obstructive pulmonary disease, tuberculosis), determined obesity using body mass index (BMI) and tested HIV status, in women newly diagnosed with breast cancer between January 2016 and April 2018 in five public hospitals in South Africa. We identified determinants of ≥2 of the seven above-mentioned conditions (defined as multimorbidity), multimorbidity itself with stage at diagnosis (advanced [III-IV] vs. early [0-II]) and multimorbidity with treatment modalities received. Among 2,281 women, 1,001 (44%) presented with multimorbidity. Obesity (52.8%), hypertension (41.3%), HIV (22.0%) and diabetes (13.7%) were the chronic conditions that occurred most frequently. Multimorbidity was more common with older age (OR = 1.02; 95% CI 1.01-1.03) and higher household socioeconomic status (HSES) (OR = 1.06; 95% CI 1.00-1.13). Multimorbidity was not associated with advanced-stage breast cancer at diagnosis, but for self-reported hypertension there was less likelihood of being diagnosed with advanced-stage disease in the adjusted model (OR 0.80; 95% CI 0.64-0.98). Multimorbidity was associated with first treatment received in those with early-stage disease, p = 0.003. The prevalence of multimorbidity is high among patients with breast cancer. Our findings suggest that multimorbidity had a significant impact on treatment received in those with early-stage disease. There is need to understand the impact of multimorbidity on breast cancer outcomes.

Association of genetic variants in CHEK2 with oesophageal squamous cell carcinoma in the South African Black population.

Oesophageal squamous cell carcinoma (OSCC) has a high incidence in southern Africa and a poor prognosis. Limited information is available on the contribution of genetic variants in susceptibility to OSCC in this region. However, recent genome-wide association studies have identified multiple susceptibility loci in Asian and European populations. In this study, we investigated genetic variants from seven OSCC risk loci identified in non-African populations for association with OSCC in the South African Black population. We performed association studies in a total of 1471 cases and 1791 controls from two study sample groups, which included 591 cases and 852 controls from the Western Cape and 880 cases and 939 controls from the Johannesburg region in the Gauteng province. Thereafter, we performed a meta-analysis for 11 variants which had been genotyped in both studies. A single nucleotide polymorphism in the CHEK2 gene, rs1033667, was significantly associated with OSCC [P = 0.002; odds ratio (OR) = 1.176; 95% confidence interval (CI): 1.06-1.30]. However, single nucleotide polymorphisms in the CASP8/ALS2CR12, TMEM173, PLCE1, ALDH2, ATP1B2/TP53 and RUNX1 loci were not associated with the disease (P > 0.05). The lack of association of six of these loci with OSCC in South African populations may reflect different genetic risk factors in non-African and African populations or differences in the genetic architecture of African genomes. The association at CHEK2, a gene with key roles in cell cycle regulation and DNA repair, in an African population provides further support for the contribution of common genetic variants at this locus to the risk of oesophageal cancer.

Liver cancer mortality trends in South Africa: 1999-2015.

BACKGROUND: In South Africa (SA), liver cancer (LC) is a public health problem and information is limited. METHODS: Joinpoint regression analysis was computed for the most recent LC mortality data from Statistics South Africa (StatsSA), by age group, sex and population group. The mortality-to-incidence ratios (MIRs) were calculated as the age-adjusted mortality rate divided by the age-adjusted incidence rate. RESULTS: From 1999 to 2015, the overall LC mortality significantly decreased in men (- 4.9%) and women (- 2.7%). Overall a significant decrease was noted in black African men aged 20-29 and 40-49 years, and white women older than 60 years but mortality rates increased among 50-59 and 60-69 year old black African men (from 2010/2009-2015) and women (from 2004/2009-2015). The mortality rates increased with age, and were higher among blacks Africans compared to whites in all age groups - with a peak black African-to-white mortality rate ratio of six in men and three in women at ages 30-39 years. The average MIR for black African men and women was 4 and 3.3 respectively, and 2.2 and 1.8 in their white counterparts. Moreover, decreasing LC mortality rates among younger and the increase in rates in older black Africans suggest that the nadir of the disease may be near or may have passed. CONCLUSIONS: Findings of population-age subgroup variations in LC mortality and the number of underdiagnosed cases can inform surveillance efforts, while more extensive investigations of the aetiological risk factors are needed. IMPACT: There was a large race, sex and age differences in trends of LC mortality in SA. These findings should inform more extensive evaluation of the aetiology and risk factors of LC in the country in order to guide control efforts.