Research co-led by OICR is helping advance understanding of the biology behind prostate cancer spreading.
Why do some prostate cancers grow slowly for years, while others progress quickly to life-threatening metastatic disease?
An international team of researchers co-led by Ontario Institute for Cancer Research (OICR) and the University of Copenhagen has uncovered new clues in the genomes of prostate cancers.
They built a comprehensive catalogue of genetic alterations that may drive prostate cancer, including alterations associated with metastatic disease. The study also uncovered previously unknown genetic alterations that may drive cancer and four genomic subtypes associated with different clinical outcomes.
“Previous studies have largely focused on mutations in known cancer genes, but many important changes occur elsewhere in the genome,” says Dr Jüri Reimand, Senior Principal Investigator at OICR, Associate Professor at the University of Toronto, and one of the senior authors of the study. “By studying the entire cancer genome and combining our knowledge about different types of genetic changes with clinical data about patient outcomes, we can better understand what drives prostate cancer and why some tumours are more aggressive than others.”
In the study, published in Nature Communications, Reimand and colleagues used computational methods to analyse whole-genome sequencing data from nearly 1,000 prostate tumours. They found that 97 per cent of tumours carried at least one genetic alteration identified as a known or potential cancer driver. The alterations included changes in established cancer genes such as PTEN and MYC, as well as previously unrecognised candidate drivers outside protein-coding regions of the genome. One particularly interesting discovery involved “enhancer hijacking,” where changes in the structure of DNA bring genetic switches called enhancers close to cancer-promoting genes, potentially activating them. The researchers found that enhancers associated with solute carrier genes, involved in cellular membrane transport, were frequently involved in these rearrangements.
The researchers also identified four distinct genomic subtypes of prostate cancer based on patterns of genetic alterations. Two of these subtypes were associated with a substantially higher risk of metastasis, highlighting their potential relevance to clinical care. The researchers also identified potential targets for existing cancer drugs in nearly one quarter of the tumours, suggesting opportunities for future targeted treatments.
“With further validation, these subtypes could help us better predict which patients are at risk of aggressive disease, and which may not need intensive treatment,” says Dr. Joachim Weischenfeldt, Professor in the University of Copenhagen’s Biotech Research and Innovation Centre and the study’s other lead author.
The researchers also identified notable differences in cancer drivers between different population ancestries, with specific drivers enriched in patients of African ancestry to be associated with more aggressive disease.
“Our findings show that prostate cancers can have very different genetic changes, some of which are linked to a higher risk of metastasis,” Reimand says. “Understanding these differences could help us better predict how the disease will progress and eventually guide more personalized treatment decisions.”
The Nature Communications paper marks the latest publication from the Pan Prostate Cancer Group (PPCG), an international collaboration studying prostate cancer genomics. Reimand and Weischenfeldt also recently co-led a study published in Nature that identified characteristic patterns of genetic mutations, or “fingerprints,” associated with aggressive prostate cancer. The PPCG consortium has assembled genomic and clinical data from approximately 2,000 prostate cancer patients across nine countries.
