Regional Variation in the Tumor Microenvironment, Immune Escape and Prognostic Factors in Breast Cancer in Sub-Saharan Africa.

The low overall survival rates of patients with breast cancer in sub-Saharan Africa (SSA) are driven by regionally differing tumor biology, advanced tumor stages at diagnosis, and limited access to therapy. However, it is not known whether regional differences in the composition of the tumor microenvironment (TME) exist and affect patients' prognosis. In this international, multicentre cohort study, 1,237 formalin-fixed, paraffin-embedded breast cancer samples, including samples of the "African Breast Cancer-Disparities in Outcomes (ABC-DO) Study," were analyzed. The immune cell phenotypes, their spatial distribution in the TME, and immune escape mechanisms of breast cancer samples from SSA and Germany (n = 117) were investigated using histomorphology, conventional and multiplex IHC, and RNA expression analysis. The data revealed no regional differences in the number of tumor-infiltrating lymphocytes (TIL) in the 1,237 SSA breast cancer samples, while the distribution of TILs in different breast cancer IHC subtypes showed regional diversity, particularly when compared with German samples. Higher TIL densities were associated with better survival in the SSA cohort (n = 400), but regional differences concerning the predictive value of TILs existed. High numbers of CD163+ macrophages and CD3+CD8+ T cells accompanied by reduced cytotoxicity, altered IL10 and IFNγ levels and downregulation of MHC class I components were predominantly detected in breast cancer samples from Western SSA. Features of nonimmunogenic breast cancer phenotypes were associated with reduced patient survival (n = 131). We therefore conclude that regional diversity in the distribution of breast cancer subtypes, TME composition, and immune escape mechanisms should be considered for therapy decisions in SSA and the design of personalized therapies. See related Spotlight by Bergin et al., p. 705.

A very-hot food and beverage thermal exposure index and esophageal cancer risk in Malawi and Tanzania: findings from the ESCCAPE case-control studies.

BACKGROUND: Consumption of very-hot beverages/food is a probable carcinogen. In East Africa, we investigated esophageal squamous cell carcinoma (ESCC) risk in relation to four thermal exposure metrics separately and in a combined score. METHODS: From the ESCCAPE case-control studies in Blantyre, Malawi (2017-20) and Kilimanjaro, Tanzania (2015-19), we used logistic regression models adjusted for country, age, sex, alcohol and tobacco, to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for self-reported thermal exposures whilst consuming tea, coffee and/or porridge. RESULTS: The study included 849 cases and 906 controls. All metrics were positively associated with ESCC: temperature of drink/food (OR 1.92 (95% CI: 1.50, 2.46) for 'very hot' vs 'hot'), waiting time before drinking/eating (1.76 (1.37, 2.26) for <2 vs 2-5 minutes), consumption speed (2.23 (1.78, 2.79) for 'normal' vs 'slow') and mouth burning (1.90 (1.19, 3.01) for ≥6 burns per month vs none). Amongst consumers, the composite score ranged from 1 to 12, and ESCC risk increased with higher scores, reaching an OR of 4.6 (2.1, 10.0) for scores of ≥9 vs 3. CONCLUSIONS: Thermal exposure metrics were strongly associated with ESCC risk. Avoidance of very-hot food/beverage consumption may contribute to the prevention of ESCC in East Africa.

Geophagia and risk of squamous cell esophageal cancer in the African esophageal cancer corridor: Findings from the ESCCAPE multicountry case-control studies.

Geophagia, the intentional practice of consuming soil, occurs across the African esophageal cancer corridor, particularly during pregnancy. We investigated whether this practice is linked to endemic esophageal squamous cell carcinoma (ESCC) in this region. We conducted ESCC case-control studies in Tanzania, Malawi and Kenya. Cases were patients with incident histologically/clinically confirmed ESCC and controls were hospital patients/visitors without digestive diseases. Participants were asked if they had ever eaten soil (never/regularly/pregnancy-only). Odds ratios (OR) are adjusted for sex, age, tobacco, alcohol, country, religion and marital status. Overall, 934 cases (Malawi 535, Tanzania 304 and Kenya females 95) and 995 controls provided geophagia information. Among controls, ever-geophagia was common in women (Malawi 49%, Kenya 43% and Tanzania 29%) but not in men (10% Malawi, <1% Tanzania). In women, ESCC ORs were 1.25 (95% CI: 0.70, 2.22) for regular versus never geophagia and 0.88 (95% CI: 0.64, 1.22) for pregnancy-only versus never. Findings were stronger based on comparisons of cases with hospital visitor controls and were null using hospital patients as controls. In conclusion, geophagia is too rare to contribute to the male ESCC burden in Africa. In women, the practice is common but we did not find consistent evidence of a link to ESCC. The study cannot rule out selection bias masking modest effects. Physical effects of geophagia do not appear to have a large impact on overall ESCC risk. Research with improved constituent-based geophagia exposure assessment is needed.

Genome-Wide DNA Methylation Profiling of Esophageal Squamous Cell Carcinoma from Global High-Incidence Regions Identifies Crucial Genes and Potential Cancer Markers.

Epigenetic mechanisms such as aberrant DNA methylation (DNAme) are known to drive esophageal squamous cell carcinoma (ESCC), yet they remain poorly understood. Here, we studied tumor-specific DNAme in ESCC cases from nine high-incidence countries of Africa, Asia, and South America. Infinium MethylationEPIC array was performed on 108 tumors and 51 normal tissues adjacent to the tumors (NAT) in the discovery phase, and targeted pyrosequencing was performed on 132 tumors and 36 NAT in the replication phase. Top genes for replication were prioritized by weighting methylation results using RNA-sequencing data from The Cancer Genome Atlas and GTEx and validated by qPCR. Methylome analysis comparing tumor and NAT identified 6,796 differentially methylated positions (DMP) and 866 differential methylated regions (DMR), with a 30% methylation (Δß) difference. The majority of identified DMPs and DMRs were hypermethylated in tumors, particularly in promoters and gene-body regions of genes involved in transcription activation. The top three prioritized genes for replication, PAX9, SIM2, and THSD4, had similar methylation differences in the discovery and replication sets. These genes were exclusively expressed in normal esophageal tissues in GTEx and downregulated in tumors. The specificity and sensitivity of these DNAme events in discriminating tumors from NAT were assessed. Our study identified novel, robust, and crucial tumor-specific DNAme events in ESCC tumors across several high-incidence populations of the world. Methylome changes identified in this study may serve as potential targets for biomarker discovery and warrant further functional characterization. SIGNIFICANCE: This largest genome-wide DNA methylation study on ESCC from high-incidence populations of the world identifies functionally relevant and robust DNAme events that could serve as potential tumor-specific markers. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2612/F1.large.jpg.

Rising Prostate Cancer Incidence in Sub-Saharan Africa: A Trend Analysis of Data from the African Cancer Registry Network.

BACKGROUND: Prostate cancer is the leading cancer in men in sub-Saharan Africa (SSA) regarding incidence and mortality. Published data from a few registries in SSA suggest that the rates are still rising, but there is little comprehensive information on the time trends of prostate cancer incidence. METHODS: We analyzed registry data on 13,170 incident prostate cancer cases in men aged 40 years or above, from 12 population-based cancer registries in 11 SSA countries, with at least a 10-year time span of comparable data. RESULTS: We observed an increase in cumulative risks (CR) and age-standardized incidence rates (ASR) over time in all registries (statistically significant in all but one). The highest values of CR were found in Seychelles and Harare (Zimbabwe). The highest annual increase in the ASRs was seen in Seychelles and Eastern Cape (South Africa), whereas the lowest was seen in Mauritius. We mainly found a steady increase in incidence with age and during successive periods. CONCLUSIONS: This analysis reveals that prostate cancer incidence rates are rising in many populations in SSA-often very rapidly-which is in contrast to recent observations worldwide. We acknowledge that the reasons are multifactorial and largely remain unclear, but believe that they are primarily associated with improvements in health care systems, for example, a broader use of prostate-specific antigen testing. IMPACT: This study is the first to compare population-level data on time trends of prostate cancer incidence between multiple countries of SSA, presenting the different rates of increase in 11 of them.

The evolving epidemic of breast cancer in sub-Saharan Africa: Results from the African Cancer Registry Network.

Breast cancer (BC) is the leading cause of cancer in sub-Saharan Africa (SSA) with rapidly increasing incidence rates reported in Uganda and Zimbabwe. However, the magnitude of these rising trends in premenopausal and postmenopausal women is unknown in most African countries. We used data from the African Cancer Registry Network on incident breast cancers in women from 11 population-based cancer registries in 10 countries representing each of the four SSA regions. We explored incidence changes among women before and after age 50 by calendar period and, where possible, generational effects in this unique sub-Saharan African cohort. Temporal trends revealed increasing incidence rates in all registries during the study period, except in Nairobi where rates stabilised during 2010 to 2014 after rapidly increasing from 2003 to 2010 (APC = 8.5 95%, CI: 3.0-14.2). The cumulative risk varied between and within regions, with the highest risks observed in Nairobi-Kenya, Mauritius and the Seychelles. There were similar or more rapidly increasing incidence rates in women aged 50+ compared to women <50 years in all registries except The Gambia. Birth cohort analyses revealed increases in the incidence rates in successive generations of women aged 45 and over in Harare-Zimbabwe and Kampala-Uganda. In conclusion, the incidence of BC is increasing rapidly in many parts of Africa; however, the magnitude of these changes differs. These results highlight the need for urgent actions across the cancer continuum from in-depth risk factor studies to provision of adequate therapy as well as the necessity of supporting the maintenance of good quality population-based cancer registration in Africa.

Three-year cancer incidence in Blantyre, Malawi (2008-2010).

In this paper, we present incidence rates of different cancers calculated for the population of Blantyre, Malawi for the period 2008-2010, using data from the Malawi Cancer Registry. Active methods were used for case finding, with standard checks for accuracy and validity performed in CanReg 4. During this 3-year period, a total of 3,711 cases were registered comprising 1,643 men (an estimated age-standardized incidence rate (ASR) of 169.8 per 100,000) and 2,068 women (ASR 238.7 per 105 ). Kaposi sarcoma (KS) was the most common cancer in men (40.5% of all cancers in men; ASR 54.0 per 105 ) while cervical cancer was the commonest in women (33.3%; ASR 88.6 per 105 ). The incidence rates for esophageal cancer remain one of the highest in the world (ASR 30.9 per 100,000 in men, 22.1 per 100,000 in women). Incidence of cancer of the prostate is relatively low in Blantyre (5.1%; ASR 16.4 per 105 ), compared with elsewhere in Africa. In childhood, the cancer spectrum is dominated by Burkitt lymphoma (32.5% ASR 90.9 per 106 ) followed by Wilms tumor (11.3%; ASR 35.9 per 106 ) and pediatric KS (11.0%; ASR 31.1 per 106 ). The overall percentage of cases with histological verification was 47.5%, a slight improvement from 42.4% in late 1990s also indicating successful case finding outside laboratories.

Genetic analysis of circulating and sequestered populations of Plasmodium falciparum in fatal pediatric malaria.

Falciparum malaria is characterized by cytoadherence of host erythrocytes containing mature asexual-stage parasites and the consequent sequestration of these forms in tissue microvasculature. A postmortem study of pediatric malaria provided us with the opportunity to compare the genetic complexity of circulating and sequestered Plasmodium falciparum populations, in patients with fatal cerebral malaria (CM) versus control subjects with incidental P. falciparum parasitemia who died of causes other than malaria. Parasite genotypes identified in peripheral blood collected at the time of admission to the hospital constituted a subset of those detected in the tissues at death. Despite a higher tissue burden of parasitized erythrocytes in patients with CM than in parasitemic control subjects, parasite populations in tissues from patients with CM were less genetically complex, and the genotypes were more homogeneously distributed throughout the body, than in patients with incidental infection. Our findings support the notion that CM is associated with the emergence of a small number of dominant genotypes in an infected individual.

Suicide in Blantyre, Malawi (2000-2003).

In an attempt to identify at risk individuals, we analysed available information for individuals who committed suicide in Blantyre, Malawi. A retrospective audit of suicides autopsied at the Queen Elizabeth Central Hospital and the University of Malawi College of Medicine mortuaries between January 2000 and December 2003 was analysed by age, sex, residential location, and mode of suicide. Eighty-four suicide cases (65 males, 19 females) represented 17% of all autopsies. The major mode of suicide in Blantyre was chemical poisoning using an agricultural pesticide, accounting for 66 cases (79%)-49 males (76%), 17 females (89%). There were no cases of poisoning by therapeutic medicines, self-immolation or incised wounds. The majority of cases were from one major urban area, Limbe, and one peri-urban area, Chileka. The demographics of suicide in Malawi differ from those reported for other African countries (e.g., lower proportion of females, no use of therapeutic medicine in poisoning, few gunshots). This audit highlights a need for investigations into the sale and use of agricultural pesticides. A prospective study of social and demographic factors around suicide should be undertaken to target groups at highest risk.

Sampling of supraorbital brain tissue after death: improving on the clinical diagnosis of cerebral malaria.

The clinical diagnosis of cerebral malaria in Plasmodium falciparum-endemic regions is strengthened by demonstration of cerebral sequestration at autopsy. Parasitized comatose patients dying of other causes are less likely to have cerebral sequestration but can be difficult to distinguish, on clinical grounds, from patients dying of cerebral malaria. Sequestered parasites in a cytological preparation of a supraorbital brain sample, obtained after death, can be studied by use of standard thin blood-film staining. We show that, when confirmation by autopsy is not possible, this procedure is a reliable surrogate for histological study of tissue and that it can accurately identify patients with or without sequestered parasites in cerebral capillaries.