M. Iqbal Parker

The T-box transcription factor Tbx2: its role in development and possible implication in cancer.

Tbx2 is a member of the T‐box family of transcription factors that are crucial in embryonic development. Recent studies suggest that T‐box factors may also play a role in controlling cell cycle progression and in the genesis of cancer. Tbx2 has been implicated in several developmental processes such as coordinating cell fate, patterning and morphogenesis of a wide range of tissues and organs including limbs, kidneys, lungs, mammary glands, heart, and craniofacial structures. Importantly, Tbx2 is overexpressed in several cancers including melanoma, small cell lung carcinoma, breast, pancreatic, liver, and bladder cancers and can suppress senescence, a cellular process, which serves as a barrier to cancer development. This review presents a state of the art overview of the role and regulation of Tbx2 in early embryonic development and in cancer.

Screening of variants for lactase persistence/non-persistence in populations from South Africa and Ghana

BackgroundLactase non-persistence is a condition where lactase activity is decreased in the intestinal wall after weaning. In European derived populations a single nucleotide polymorphism (SNP) C/T-13910 residing 13.9 kb upstream from the lactase gene has been shown to define lactase activity, and several other single nucleotide polymorphisms (G/C-14010 T/G-13915, C/G-13907 and T/C-13913) in the same region have been identified in African and Middle East populations.ResultsThe T-13910 allele most common in European populations was present in 21.8% mixed ancestry (N = 62) individuals and it was absent in the Xhosa (N = 109) and Ghana (N = 196) subjects. Five other substitutions were also found in the region covering the previously reported variants in African and Middle East populations. These included the G/C-14010 variant common in Kenyan and Tanzanian populations, which was present in 12.8% of Xhosa population and in 8.1% of mixed ancestry subjects. Two novel substitutions (C/T-14091 and A/C-14176) and one previously reported substitution G/A-13937 (rs4988234) were less common and present only in the Xhosa population. One novel substitution G/A-14107 was present in the Xhosa and Ghanaian populations. None of the other previously reported variants were identified.ConclusionIdentification of the G/C-14010 variant in the Xhosa population, further confirms their genetic relatedness to other nomadic populations members that belong to the Bantu linguistic group in Tanzania and Kenya. Further studies are needed to confirm the possible relationship of the novel substitutions to the lactase persistence trait.

The cumulative effects of polymorphisms in the DNA mismatch repair genes and tobacco smoking in oesophageal cancer risk.

The DNA mismatch repair (MMR) enzymes repair errors in DNA that occur during normal DNA metabolism or are induced by certain cancer-contributing exposures. We assessed the association between 10 single-nucleotide polymorphisms (SNPs) in 5 MMR genes and oesophageal cancer risk in South Africans. Prior to genotyping, SNPs were selected from the HapMap database, based on their significantly different genotypic distributions between European ancestry populations and four HapMap populations of African origin. In the Mixed Ancestry group, the MSH3 rs26279 G/G versus A/A or A/G genotype was positively associated with cancer (ORu200a=u200a2.71; 95% CI: 1.34–5.50). Similar associations were observed for PMS1 rs5742938 (GG versus AA or AG: ORu200a=u200a1.73; 95% CI: 1.07–2.79) and MLH3 rs28756991 (AA or GA versus GG: ORu200a=u200a2.07; 95% IC: 1.04–4.12). In Black individuals, however, no association between MMR polymorhisms and cancer risk was observed in individual SNP analysis. The interactions between MMR genes were evaluated using the model-based multifactor-dimensionality reduction approach, which showed a significant genetic interaction between SNPs in MSH2, MSH3 and PMS1 genes in Black and Mixed Ancestry subjects, respectively. The data also implies that pathogenesis of common polymorphisms in MMR genes is influenced by exposure to tobacco smoke. In conclusion, our findings suggest that common polymorphisms in MMR genes and/or their combined effects might be involved in the aetiology of oesophageal cancer.

Distinct genetic association at the PLCE1 locus with oesophageal squamous cell carcinoma in the South African population

Oesophageal squamous cell carcinoma (OSCC) has a high prevalence in the Black and Mixed Ancestry populations of South Africa. Recently, three genome-wide association studies in Chinese populations identified five new OSCC susceptibility loci, including variants at PLCE1, C20orf54, PDE4D, RUNX1 and UNC5CL, but their contribution to disease risk in other populations is unknown. In this study, we report testing variants from these five loci for association with OSCC in the South African Black (407 cases and 849 controls) and Mixed Ancestry (257 cases and 860 controls) populations. The RUNX1 variant rs2014300, which reduced risk in the Chinese population, was associated with an increased risk of OSCC in the Mixed Ancestry population [odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.09-1.63, P = 0.0055], and none of the five loci were associated in the Black population. Since PLCE1 variants increased the risk of OSCC in all three Chinese studies, this gene was investigated further by sequencing in 46 Black South Africans. This revealed 48 variants, 10 of which resulted in amino acid substitutions, and much lower linkage disequilibrium across the PLCE1 locus than in the Chinese population. We genotyped five PLCE1 variants in cases and controls, and found association of Arg548Leu (rs17417407) with a reduced risk of OSCC (OR = 0.74, 95% CI = 0.60-0.93, P = 0.008) in the Black population. These findings indicate several differences in the genetic contribution to OSCC between the South African and Chinese populations that may be related to differences in their genetic architecture.

Association of a Deletion of GSTT2B with an Altered Risk of Oesophageal Squamous Cell Carcinoma in a South African Population: A Case-Control Study

Background Polymorphisms in the Glutathione S-transferase genes are associated with altered risks in many cancers, but their role in oesophageal cancer is unclear. Recently a 37-kb deletion polymorphism of GSTT2B that reduces expression of GSTT2 has been described. We evaluated the influence of the GSTT1 and GSTT2B deletion polymorphisms, and the GSTP1 Ile105Val polymorphism (rs1695) on susceptibility to oesophageal squamous cell carcinoma (OSCC) in the Black and Mixed Ancestry populations of South Africa. Methods and Results The GSTT1, GSTT2B and GSTP1 variants were genotyped in 562 OSCC cases and 907 controls, and tested for association with OSCC and for interaction with smoking and alcohol consumption. Linkage disequilibrium (LD) between the deletions at GSTT1 and GSTT2B was determined, and the haplotypes tested for association with OSCC. Neither the GSTT1 deletion nor the GSTP1 Ile105Val polymorphism was associated with OSCC risk in the Black or Mixed Ancestry populations. The GSTT2B deletion was not associated with OSCC risk in the Black population, but was associated with reduced risk of OSCC in the Mixed Ancestry population (ORu200a=u200a0.71; 95% CI 0.57–0.90, pu200a=u200a0.004). Case-only analysis showed no interaction between the GST polymorphisms and smoking or alcohol consumption. LD between the neighboring GSTT1 and GSTT2B deletions was low in both populations (r2 Blacku200a=u200a0.04; r2 MxAu200a=u200a0.07), thus these deletions should be assessed independently for effects on disease risk. Conclusions Although there was no association between the GSTT1 deletion polymorphism or the GSTP1 Ile105Val polymorphism with OSCC, our results suggest that the presence of the recently described GSTT2B deletion may have a protective effect on the risk of OSCC in the Mixed Ancestry South African population. This is the first report of the contribution of the GSTT2B deletion to cancer risk.

MicroRNA Polymorphisms and Environmental Smoke Exposure as Risk Factors for Oesophageal Squamous Cell Carcinoma

MicroRNAs (miRNAs) and related polymorphisms have been implicated in the susceptibility to oesophageal squamous cell carcinoma (OSCC). In our study, three miRNA-related SNPs: rs6505162 A>C (pre-miRNA of miR-423), rs213210 A>G (3’UTR of miR-219-1) and rs7372209 C>T (5’UTR of miR-26a-1) were investigated in the Black and Mixed Ancestry population groups in South Africa. The potential cumulative effects of these SNPs, as well as gene-environment interactions were also analysed. In Blacks, rs6505162 A>C was associated with OSCC under dominant, additive and recessive models with odds ratios (ORs) 1.353, 1.404, and 2.858, respectively. This locus showed very strong interactions with smoke inhalation from burning wood or charcoal used for heating and cooking in very poorly ventilated areas (OR(GE)=7.855, P(GE)=9.17*10-10 in the Black group). Furthermore, the miR-423-3p level was 1.39 fold up-regulated in tumour tissues compared to the adjacent normal tissue (paired t-test P value 0.0087). SNP-SNP interaction between rs2132210 and rs7372209 was found in both Black and Mixed Ancestry subjects. The AArs213210-CTrs7372209 genotype had a protective effect on OSCC risk (in the Black, OR=0.229, P=0.012; and the Mixed Ancestry groups, OR=0.230, P=0.00014). This study is the first to link SNPs in miR-423 together with environmental smoke exposure to risk for developing OSCC.

Aberrant methylation of the MSH3 promoter and distal enhancer in esophageal cancer patients exposed to first-hand tobacco smoke

AbstractPurposenPolymorphisms in MSH3 gene confer risk of esophageal cancer when in combination with tobacco smoke exposure. The purpose of this study was to investigate the methylation status of MSH3 gene in esophageal cancer patients in order to further elucidate possible role of MSH3 in esophageal tumorigenesis.MethodsWe applied nested methylation-specific polymerase chain reaction to investigate the methylation status of the MSH3 promoter in tumors and matching adjacent normal-looking tissues of 84 esophageal cancer patients from a high-risk South African population. The Cancer Genome Atlas data were used to examine DNA methylation profiles at 17 CpG sites located in the MSH3 locus.ResultsOverall, promoter methylation was detected in 91.9xa0% of tumors, which was significantly higher compared to 76.0xa0% in adjacent normal-looking esophageal tissues (Pxa0=xa00.008). When samples were grouped according to different demographics (including age, gender and ethnicity) and smoking status of patients, methylation frequencies were found to be significantly higher in tumor tissues of Black subjects (Pxa0=xa00.024), patients of 55–65xa0years of age (Pxa0=xa00.032), males (Pxa0=xa00.037) and tobacco smokers (Pxa0=xa00.015). Furthermore, methylation of the MSH3 promoter was significantly more frequent in tumor samples from smokers compared to tumor samples from non-smokers [odds ratio (OR)xa0=xa031.9, Pxa0=xa00.031]. The TCGA data confirmed significantly higher DNA methylation level at the MSH3 promoter region in tumors (Pxa0=xa00.0024). In addition, we found evidence of an aberrantly methylated putative MSH3-associated distal enhancer element.ConclusionOur results suggest that methylation of MSH3 together with exposure to tobacco smoke is involved in esophageal carcinogenesis. Due to the active role of the MSH3 protein in modulating chemosensitivity of cells, methylation of MSH3 should further be examined in association with the outcome of esophageal cancer treatment using anticancer drugs.

Progression of esophageal dysplasia to cancer.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the evolution of low‐grade squamous and glandular dysplasia to invasive carcinoma; the mutational spectra of Barretts esophagus and adenocarcinoma; the risk of p53‐immunoreactive glandular dysplasia compared to non‐immunoreactive mucosa for progression to cancer; the role of lectins in progression to adenocarcinoma; and the role of racemase immunoreactivity in the prediction of risk of adenocarcinoma.

Health research in Africa: getting priorities right.

Le profil des maladies en Afrique subsaharienne change et de nombreux pays sont confrontés à une nouvelle et croissante menace par des maladies non transmissibles. La plupart des prédictions du changement du profil des maladies en Afrique subsaharienne ont été jusqu’à présent fondées sur des extrapolations simples de l’histoire des pays industrialisés du Nord. Cette revue présente une vision plus large et décrit comment l’interaction entre les maladies infectieuses et non infectieuses, des facteurs génétiques spécifiques et une distribution déséquilibrée des ressources pour la recherche en santé, peuvent alimenter une nouvelle crise sanitaire non nécessaire dans de grandes parties de l’Afrique. Pour éviter cela, la perception traditionnelle de la santé humaine et le bien‐être en Afrique devrait changer drastiquement. Cependant, plus de 90% du financement de la recherche en santé en Afrique subsaharienne reste consacré au VIH/SIDA, au paludisme et à la tuberculose. Qu’est‐ce qui n’a pas marché dans l’établissement des priorités et comment pouvons‐nous changer cela?

The African Esophageal Cancer Consortium: A Call to Action

Esophageal cancer is the eighth most common cancer worldwide and the sixth most common cause of cancer-related death; however, worldwide incidence and mortality rates do not reflect the geographic variations in the occurrence of this disease. In recent years, increased attention has been focused on the high incidence of esophageal squamous cell carcinoma (ESCC) throughout the eastern corridor of Africa, extending from Ethiopia to South Africa. Nascent investigations are underway at a number of sites throughout the region in an effort to improve our understanding of the etiology behind the high incidence of ESCC in this region. In 2017, these sites established the African Esophageal Cancer Consortium. Here, we summarize the priorities of this newly established consortium: to implement coordinated multisite investigations into etiology and identify targets for primary prevention; to address the impact of the clinical burden of ESCC via capacity building and shared resources in treatment and palliative care; and to heighten awareness of ESCC among physicians, at-risk populations, policy makers, and funding agencies.