Study uncovers genetic drivers of aggressive prostate cancer

The findings, published in Cancer Discovery, evaluated the roles of inherited genetic factors passed down from our parents and somatic mutations acquired during tumor formation. The research shows that germline and somatic variability work together to initiate and drive progression of prostate cancer. This discovery could one day help improve how doctors predict and treat aggressive cancers.

"The interaction between inherited genetic factors and the timing of mutations in the tumor's DNA is central to understanding how prostate cancer evolves," said Dr. Paul Boutros, professor of urology and human genetics at the David Geffen School of Medicine at UCLA, director of cancer data science at the UCLA Health Jonsson Comprehensive Cancer Center and co-senior author of the study. "We found that prostate cancer follows a common evolutionary path, with different tumors branching off depending on early genetic changes and an individual's inherited genetic background. Some tumors may become aggressive because of specific mutations, while others remain indolent. Both genetic randomness and inherited traits play a role in determining these outcomes."

Studying prostate cancer presents unique challenges due to its complex nature. It is one of the most common cancers, yet it has relatively few mutations, grows slowly over decades, and is difficult to detect on scans. Current methods for assessing tumor aggressiveness are limited, and treatments primarily target androgen signaling, leaving patients with few options when resistance develops. In fact, while some prostate cancers are aggressive, others grow so slowly they may never cause harm. Distinguishing between these types remains difficult, as the genetic differences underlying them have not been understood.

To fill this gap and better understand how genetic differences in prostate cancer develop over time, researchers used whole-genome sequencing to analyze the complete genomes of 666 localized prostate tumors -- the largest whole-genome dataset of its kind -- covering the full range from mild to aggressive cases. This massive dataset was over a petabyte of data, about the size of 500 million pages of text.

By creating and applying advanced machine-learning and statistical methods to this massive dataset, the researchers identified 223 regions of the genome frequently mutated in prostate tumors that help cancer grow and spread. Most of these were undetectable using traditional targeted sequencing methods deployed in clinical assays. Additionally, inherited genetic variations, known as germline SNPs, were found to influence how tumors evolve by affecting which somatic mutations are acquired during tumor development.

The researchers also found that aggressive (high-grade) and slow-growing (low-grade) grade prostate cancers are not distinct diseases but rather different stages along the same evolutionary trajectory. While both types start from the same early-stage abnormal cells and share many mutations, aggressive cancers acquire additional harmful mutations, such as BRCA2 and MYC, earlier in their development, contributing to a more aggressive trajectory.

"Until now, the extent to which inherited genetic variation contributes to somatic mutations in prostate cancer was unclear," said Takafumi Yamaguchi, a senior bioinformatician and doctoral candidate at the UCLA Health Jonsson Comprehensive Cancer Center and co-first author of the study. "But our study shows that certain germline variants can influence the likelihood of acquiring somatic driver mutations later in life. Importantly, we also discovered that certain mutations, like MYC, appear early in prostate cancer development and are linked to more aggressive forms of the disease. If these mutations occur in later stages, they may not have as significant an impact on prognosis. So, the timing of key mutations is crucial because when high-risk mutations occur earlier in a tumor's development, the cancer is more likely to relapse or spread."

These findings underscore the importance of including multi-ancestry cohorts in cancer research. Understanding how genetic background shapes tumor evolution could help improve diagnosis and treatment strategies across diverse populations.

"This study offers a new way of thinking about prostate cancer risk assessment," said Boutros, who also serves as the interim vice dean for research at the David Geffen School of Medicine at UCLA, and is the associate director of cancer informatics at the UCLA Institute for Precision Health. "By combining inherited genetic markers with tumor sequencing, we could one day more accurately predict which cancers are likely to become aggressive and uncover new ways to prevent aggressive prostate cancer before it develops."

As the next stage of research, scientists are now focusing on expanding these studies to include multi-ancestry populations, which could ultimately refine risk assessments and therapeutic strategies for prostate cancer and other cancers in diverse groups.

Additional co-first authors are Kathleen Houlahan, Helen Zhu, Natalie Kurganovs, Julie Livingstone and Natalie Fox. Additional co-senior authors are Niall Corcoran, Juri Reimand and Christopher Hovens. A full list of authors is available in the study.