Study reveals aggressive prostate cancer linked to ancestral heritage

Two pioneering studies published simultaneously today in Nature and Genome Medicine have identified genetic signatures explaining ethnic differences in the severity of prostate cancer, particularly in sub-Saharan Africa.

Through genetic sequencing of prostate cancer tumours from Australian, Brazilian and South African donors, the team identified a new prostate cancer taxonomy (classification scheme) and cancer drivers that not only distinguish patients by genetic ancestry, but also predict which cancers are likely to become life-threatening – a task that currently proves challenging.

“Our understanding of prostate cancer has been severely limited by a research focus on Western populations,” said senior author Professor Vanessa Hayes, genomicist and Petre Chair of Prostate Cancer Research at the University of Sydney’s Charles Perkins Centre and Faculty of Medicine and Health in Australia. “Being of African descent, or from Africa, more than doubles a man’s risk for lethal prostate cancer. While genomics holds a critical key to unravelling contributing genetic and non-genetic factors, data for Africa has till now, been lacking.”

“Prostate cancer is the silent killer in our region,” said the University of Pretoria’s Professor Riana Bornman, an international expert in men's health and clinical lead for the Southern African Prostate Cancer Study in South Africa.

“We had to start with a grassroots approach, engaging communities with open discussion, establishing the infrastructure for African inclusion in the genomic revolution, while determining the true extent of prostate disease.”

Through sophisticated whole genome sequencing (a way of mapping the entire genetic code of cancer cells), over two million cancer-specific genomic variants were identified in 183 untreated prostate tumours from men living across the three study regions. 

“We found Africans to be impacted by a greater number and spectrum of acquired (including cancer driver) genetic alterations, with significant implications for ancestral consideration when managing and treating prostate cancer,” said Professor Hayes. 

“Using cutting-edge computational data science which allowed for pattern recognition that included all types of cancer variants, we revealed a novel prostate cancer taxonomy which we then linked to different disease outcomes,” said Dr Weerachai Jaratlerdsiri, a computational biologist from the University of Sydney and first author on the Nature paper.

“Combining our unique dataset with the largest public data source of European and Chinese cancer genomes allowed us to, for the first time, place the African prostate cancer genomic landscape into a global context.”

As part of her PhD at the University of Sydney, Dr Tingting Gong, first author on the Genome Medicine paper, painstakingly sifted through the genomic data for large changes in the structure of chromosomes (molecules that hold genetic information). These changes are often overlooked because of the complexity involved in computationally predicting their presence, but are an area of critical importance and contribution to prostate cancer.

“We showed significant differences in the acquisition of complex genomic variation in African and European derived tumours, with consequences for disease progression and new opportunities for treatment,” said Dr Gong.

This cancer genome resource is possibly the first and largest in the world to include African data.

“Through African inclusion, we have made the first steps not only toward globalising precision medicine, but ultimately to reducing the impact of prostate cancer mortality across rural Africa,” explained Professor Bornman.

“A strength of this study was the ability to generate and process all data through a single technical and analytical pipeline,” added Professor Hayes.

The research featured in the Nature and Genome Medicine paper is part of the legacy of the late Archbishop Emeritus Desmond Tutu. He was the first African to have his complete genome sequenced, data which would be an integral part of genetic sequencing and prostate cancer research in southern Africa.

The results of the sequencing were published in Nature in 2010.

“Diagnosed at age 66 with advanced prostate cancer, to which he succumbed in late December 2021, the Archbishop was an advocate not only for prostate cancer research in southern Africa, but also the benefits that genomic medicine would offer all peoples,” recollected Professor Hayes. “We hope this study is a first step to that realisation.”

The international research team included academics from the University of Sydney in Australia, and affiliated institutions at St Vincent’s Hospital, Royal Prince Alfred Hospital, Garvan Institute of Medical Research and Chris O’Brien Lifehouse; in South Africa from the University of Pretoria, University of Limpopo, and Sefako Makgatho Health Science University, and including the Dr George Mukhari Academic Hospital, Kalafong Academic Hospital, and National Health Laboratory Services; in Brazil from Universidade Federal do Rio Grande do Sul, and from the University of Manchester in the United Kingdom, with additional contributions for the Genome Medicine paper from the University of Melbourne and the Walter and Eliza Hall Institute in Australia.

Professor Hayes acknowledges the foresight of The Petre Foundation and donor Daniel Petre, who has supported her vision for inclusive genomic research for over eight years.

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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