Study aims to address complex genomics of human diversity and prostate cancer

Gender is one of the strongest and most consistent predictors of health and life expectancy. For men, unfortunately, this is not good news. On average, across the globe, men die six years earlier than their female counterparts. Every year in November, or Movember as it has become popularly known, millions of men across the world sport a hairy upper lip to show their support for and raise awareness of men’s health issues, including prostate cancer (also referred to as carcinoma of the prostate or PCa), testicular cancer, poor mental health and physical inactivity. PCa, in particular, is the second most common cancer in men worldwide (after lung cancer), with more than 1,1 million cases recorded in 2012.

PCa is the development of malignancy (resulting from abnormal cell growth) in the prostate, which is a gland that forms part of the male reproductive system. As with most other types of cancer, PCa cells can spread from the prostate to other parts of the body, particularly to the bones and lymph nodes. Treatment, even when successful, can take a toll on the physical and mental health of those affected.

In the Western world, PCa has the highest incidence rate of all male-associated cancers and the second highest mortality rate. In African countries, including South Africa, the incidence of PCa among non-migrant Africans is uncertain, but a trend towards earlier age at diagnosis has been observed. It is estimated that among South African men, at least one in every 23 will develop PCa within their lifetime. The specific contributing factors are however still unclear and PCa incidence and mortality rates are masked dramatically by the impact of infectious disease on average life expectancy in males. Since PCa is usually a disease of older age, the prevalence in South African men is expected to increase as the average life expectancy moves closer to that reported from the West.

Population-based studies have to date almost exclusively been driven by USA research, which found that African-Americans are 1,7 times more likely to be diagnosed with PCa (and at a younger age) and 2,5 times more likely to die from PCa than Americans of European decent. The risk faced by African-Americans is even greater when compared to Asian-Americans. It is therefore critical that the true impact of PCa in South Africa is assessed and addressed appropriately.

The most significant risk factors for PCa, namely older age, family history of PCa and African ancestry, suggest that both environmental and genetic factors are likely contributors to susceptibility to and disease course in Southern African men.

In 2008 a team of clinicians and researchers from the University of Limpopo joined forces with Prof Vanessa Hayes, Head of Human Comparative and Prostate Cancer Genomics and her team at the Garvan Institute of Medical Research in Sydney, Australia. The Southern African Prostate Cancer Study (SAPCS) was subsequently established with seed funding from the South African Medical Research Council (SA MRC). Prof Riana Bornman, Senior Research Professor in the School of Health Systems and Public Health at the University of Pretoria (UP)’s Faculty of Health Sciences is the current Study Director in South Africa. Prof Don Cowan from UP’s Genomics Research Institute (GRI) and Prof Pascal Bessong from the University of Venda (UniVen) also recently joined the SAPCS with a view to determining the infectious drivers of prostate cancer in South African men. Through these collaborative efforts, both nationally (with the GRI and UniVen) and internationally (with Prof Hayes and her team at the Garvan Institute), the UP team has access to the most state-of-the-art technology available to address the complex genomics of early-derived human diversity and PCa. The SAPCS data, which is a unique resource of epidemiological, genetic and clinical data, are for the first time shedding light on the scope and impact of PCa in the central to northern regions of South Africa.

Prof Hayes, who also holds an extraordinary professorship at the School of Health Systems and Public Health, led the team that made headline news in 2010 by generating the first complete personalised human DNA sequences (human genomes) for Africa, including that of Nobel Peace Laureate Archbishop Desmond Tutu. These African genomes are providing the framework for disease studies and drug development tailored for Africa.

Certain areas on the human genome have been identified as indicating the risk of developing PCa. In the pilot study of 837 men, which addressed the contribution of previously described genetic and epidemiological risk factors associated with increased PCa risk and aggressive disease in men from South Africa, these genetic risk factors (largely European defined) showed no evidence for disease prediction. The team also found that black South African men presented with higher prostate-specific antigen (PSA) levels (a biomarker in blood that could indicate PCa) and more aggressive PCa which is further escalated in men from rural localities. The data suggests that a lack of PSA testing may be contributing to an aggressive PCa disease phenotype in South African men. Genome-wide approaches are crucial to defining African-specific risk areas and the genomic signature of PCa observed in South Africa.

Driven by an observed link between maternal inheritance and PCa risk, the SAPCS recently turned their attention to the maternally inherited mitochondrial genome. In a first-of-its-kind study, the team investigated the impact of mitochondrial genome variation in South African men with different presentations of PCa. Through this project (funded by the USA National Institute of Health (NIH), the team has doubled the total number of PCa-associated mitochondrial DNA mutations identified globally. In addition, they reported that the total number and frequency of somatic mitochondrial mutations offer predictive power to determine aggressive prostate cancer in South African men (based on a Gleason score either equal to or greater than 7). The study has been accepted for publication in the journal, The Prostate and its results were recently discussed at the SAPCS’ Inaugural Workshop that was held at UP in October 2015. Members, students and prospective scientific collaborators did presentations on aspects of PCa of interest to them and the team discussed the way forward.

Prof Bornman points out that they are specifically trying to find early markers of PCa in African men because current PSA testing is not as useful in African men as in men from European ancestry. PSA is a protein produced by cells in the prostate and levels higher than normal are helpful in indicating men who should undergo a prostate biopsy. It is important to note that PSA testing alone is not sufficient to rule out PCa; a digital rectal examination of the prostate should also be normal to rule out the disease. PSA testing is however not always freely available in remote rural areas of South Africa, which means that by the time many African men are eventually diagnosed with prostate cancer, the disease may have spread beyond the prostate, which limits treatment options considerably. For this reason, says Prof Bornman, it is vital for us to find markers that are specific to African men to assist in the timely diagnosis of this devastating disease.

An understanding of, inter alia, the genomic signatures of PCa in the indigenous populations of Africa, may yield invaluable information on direct efforts to limit disease predisposition and development in men from the African continent and African-Americans. It may also open new avenues of early diagnosis and treatment to improve life expectancy.

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Researchers

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  Professor Riana Bornman

  Professor Riana Borman’s research seeks to understand the effects of endocrine-disrupting chemicals (EDCs) on human and environmental health, with a special focus on male reproduction. Most of her research is carried out in the rural areas of the Vhembe District in Limpopo, in communities where insecticide is sprayed to control malaria-carrying mosquitoes.
  She began her career in the Department of Urology at the University of Pretoria (UP) in 1980 and had a research topic to explore within the first week, which triggered a career-long curiosity. “I am still researching the role of EDCs on human health today,” she says.
  
  Prof Bornman, who obtained an MBChB at UP, says her research focus developed from her experiences in managing patients in clinical settings. “As a clinical physician, I realised that human and environmental health was intricately affected by environmental pollution, especially exposure to EDCs. Being a clinician at UP has created unique opportunities to conduct research in the Limpopo province.”
  
  Her field of research addresses the unintentional health consequences of annual indoor residual spraying of insecticides to control malaria-carrying mosquitoes. In the Vhembe District, dichlorodiphenyltrichloroethane (DDT) is sprayed to control these mosquitoes and reduce cases of malaria and death. While DDT is largely a banned chemical, according to the Stockholm Convention on Persistent Organic Pollutants, it is allowed in some countries, including South Africa, for malaria vector control.
  But there is growing concern around the adverse health effects associated with DDT. Scientific evidence from South Africa is crucial and contributes to the body of evidence that is calling for safer alternatives to DDT for malaria vector control.
  
  The chemical is effective for about six months and needs to be sprayed every year. Prof Bornman’s research shows that annual spraying has negative, long-term consequences for pregnant women and young children. “We are seeing these consequences in children, possibly persisting into future generations, suggesting long-term health effects. Our research collects important irrefutable scientific evidence of the health impacts of EDCs in communities exposed to insecticides.”
  
  Prof Bornman is the co-principal investigator for the Venda Health Examination of Mothers, Babies and the Environment (VHEMBE) study, which is being conducted in collaboration with Prof Brenda Eskenazi of the University of California, Berkeley in the US and Dr Jonathan Chevrier of McGill University, Canada. The VHEMBE study is the first birth cohort from a population that is currently exposed to DDT via annual spraying and is the biggest longitudinal birth cohort from Africa. The study group recruited and enrolled 752 mother-child pairs at Tshilidzini Hospital in Thohoyandou and have monitored the children up to eight and a half years of age for various possible health impacts.
  
  She hopes to continue doing research that contributes to improving the health of those whose voices are not often heard.
  
  She is also co-principal investigator and clinical leader of the South African Prostate Cancer Study, which is investigating the genomics of prostate cancer in African men; this is being done in partnership with Prof Vanessa Hayes, Scientific Director of the Garvan Institute of Medical Research in Sydney, Australia. A recent highlight in their research work has been funding awards from major international bodies to investigate the development of aggressive prostate cancer in black African men. “We are extremely motivated to continue with this research,” says Prof Bornman. “Successful awards reflect that the scientific leaders in our field support our approach.”
  
  Over the past 18 months, the prostrate cancer study group began a new project that focuses on the mutational signatures of DDT and the possible role of this EDC on prostate cancer aetiology. Prof Bornman is also the study leader for a new study on knowledge, attitudes and practices of traditional healers, primary healthcare service providers and men in the rural Vhembe District.
  
  She says in her research work she was inspired by Prof Dion du Plessis, former Head of Urology and Dean of the Faculty of Health Sciences at UP, who taught her to think beyond the obvious, to dream big and to just DO it!
  Her academic role model was Prof Carl Franz, former Head of Surgery at UP. He was a prime example of how to integrate laboratory and clinical medicine in an academic career, she says.
  
  Her message to school learners or undergraduates who are interested in her field is: “Every one of us, irrespective of our discipline, can make a difference in the lives of people. My research aims to improve the lives of people living with the constant threat of malaria under unforgiving environmental and socio-economic conditions. We can all do research that makes a difference. One just has to care enough about people.”
  
  Her hobbies are photography and travel.
  
  
  

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