Simultaneous Spurts of Mutations Drive Prostate Cancer, Whole-Genome Sequencing Study Finds

A large collaborative research effort shows that prostate cancers may evolve in sudden, brief spurts of many simultaneous genetic mutations that disrupt important prostate cancer genes. Using deep-sequencing techniques and computer modeling, scientists have created a detailed temporal map of how genetic aberrations evolve within prostate tumors. This result differs from the traditional model of cancer resulting from the step-by-step accumulation of individual mutations. The study is published in the journal Cell.

In an effort to understand the details of the genetic evolution of localized prostate tumors into invasive and metastatic disease, Mark Rubin, MD, at the Department of Pathology, Weill Cornell Medical College in New York; Levi Garraway, MD, PhD at the Broad Institute and Dana-Farber Cancer Institute in Massachusetts; and Francesca Demichelis, PhD, an assistant professor at the Centre for Integrative Biology at the University of Trento in Italy sequenced 57 prostate tumors. They matched the tumor tissue with normal patient tissue to study how tumors accumulate mutations.

Through whole-genome sequencing and analysis of DNA copy number, the team found that early prostate cancer genomes already had many deletions. These early prostate cancer genomes also had many chromosomal translocations. This type of mutation occurs when one or several chromosomal breaks occur and two chromosomal break-ends fuse together, either from the same or different chromosomes. Translocations are frequent in cancer—a well-known translocation is the Philadelphia chromosome, which occurs in chronic myelogenous leukemia when the ABL1 gene on chromosome 9 is fused to the BCR gene on chromosome 22.

The researchers named the complex chromosomal rearrangements they observed “chromoplexy.” Computer modeling of the observed rearrangements suggested that such chromosomal scrambling could occur as a result of only a few events in the evolution of a prostate tumor and cause disruptions of several important prostate cancer genes at once, rather than in a stepwise manner.

“We believe that our study on chromoplexy and earlier studies suggest that punctuated and catastrophic models of mutational evolution are important in some types of cancer,” Rubin says.  “In prostate cancer, chromoplexy appears as a major mechanism for disease progression.”

Fifty-five of the tumor samples were from untreated patients and ranged from early to late stage cancers; two metastatic tumor samples were from patients who progressed after castration-based therapy. Having surveyed a range of different disease stages, the team proposes that the bulk of chromosomal rearrangements occur early in prostate cancer progression.  Rubin, who is also the director of the recently established Institute for Precision Medicine at the Cornell Medical School in NYC, says that the next step is to analyze serial biopsies from patients throughout their treatments to address how chromoplexy evolves in response to treatment.

Mutations that deactivate tumor suppressor genes, which normally prevent development of tumors, are frequently found in prostate cancers. The study authors found that the tumor suppressor genes PTEN, TP53, and CDKN1B were rearranged or deleted as a result of chromoplexy in the tumor samples. They also found that prostate tumors classified as ‘high-grade’ were more likely to have massive rearrangements and copy number changes compared to lower-grade histology tumors.

Rubin believes that whole-genome analysis will facilitate the identification of the major molecular drivers of aggressive prostate cancer. “These types of studies should help inform us as to which tumor genes we need to study more carefully,” he says.

The authors suggest that more aggressive tumors may experience an early ‘catastrophic’ event that leads to more genomic rearrangements and disruptions of important cancer-curbing processes more quickly. Further research is required to support this hypothesis.

An important remaining question is how best to distinguish those prostate cancer patients who have indolent disease and are therefore candidates for active surveillance, from those with aggressive disease who need aggressive treatment. It is likely that some men currently being treated for prostate cancers could actually forgo treatments that come with many adverse side effects

Besides continuing to understand how chromoplexy affects prostate cancer progression, Rubin and colleagues are now working on exploring the prevalence of chromoplexy in other cancers.