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Study Indicates Genetic Changes Arise Abruptly in Prostate Cancer

NEW YORK (GenomeWeb News) – Genetic mutations in prostate cancer appear to arise all of a sudden, a team of investigators led by Weill Cornell Medical College's Mark Rubin; Levi Garraway of Harvard Medical School, the Broad Institute, and Dana-Farber Cancer Institute; and Francesca Demichelis from the University of Trento in Italy, reported in Cell yesterday.

The appearance of these mutations occur in a manner similar to how the concept of punctuated equilibrium envisions the evolution of species —a long spell of little-to-no evolution followed by a rapid accrual of changes, the group added.

The team analyzed genomic rearrangements in nearly 60 prostate cancer genomes and matched controls and found that many DNA translocations and deletions that affected a number of cancer-related genes occurred in what appeared to be an interdependent manner, a process the group dubbed "chromoplexy." The group also traced back the accumulation of mutations in the cancer genomes to tease out the order in which chromoplexy events took place and to identify such bursts of rearrangement activity.

"Chromoplexy is a common process by which geographically-distant genomic regions may be disrupted at once, in a coordinated fashion," Rubin said in a statement. "The unifying feature is that these alterations seem to occur in a sequential, punctuated pattern which is designed to eliminate cancer-fighting genes. This suggests that genes that are active at the end of these events may drive progression of the cancer."

Rubin and his colleagues also noted that such insights into the initiation and progression of tumors could affect the detection, prevention, and treatment of cancer.

To examine the overall landscape of genomic rearrangements in prostate cancer, the researchers sequenced 55 primary prostate adenocarcinomas and two neuroendocrine prostate cancer metastases, which they then mapped to the reference genome. They also sequenced paired normal tissue.

The researchers found nearly 5,600 rearrangements in tumor tissue that was absent from normal tissue, and of those rearrangements 113 were validated through resequencing or PCR amplification. A number of genes, including PTEN, RB1, GSK3B, and FOXO1, underwent rearrangements that likely have biological consequences like contributing to cancer development, the researchers added.

The rearrangements also appeared to occur in chains in which breakpoints for one rearrangement then become a spot for a second rearrangement. According to a model developed by the investigators, these rearrangement chains are not likely to be independent events, but arise through a coordinated process, which they called chromoplexy.

They then developed ChainFinder, an algorithm to search for other coordinated events, and found chromoplexy-related chains of five or more events in 50 of the 57 tumors analyzed, and 36 of the 57 tumors contained two or more such chains.

Not all subsets of prostate cancer exhibited the same levels of chromoplexy. The researchers noted that tumors with ETS fusions contained more interchromosomal rearrangements than ETS- tumors. Further, a subgroup of ETS- tumors had rearrangements that more closely resembled chromothripsis, a more catastrophic shattering and repair of chromosomes in cancer. Those tumors had deletions or rearrangements affecting the CHD1 gene, a putative tumor suppressor gene though to be involved in regulating genome stability.

Indeed, a number of cancer genes commonly appear to be affected by chromoplexy events in prostate cancer. For example, PTEN was deleted or affected by a rearrangement in nine cases, NKX3-1 in eight, and TP53 in four. "[C]hromoplexy may conceivably influence prostate carcinogenesis by disrupting TSGs and creating oncogenic fusions," the researchers noted.

In addition, chromoplexy events may affect a number of cancer-related genes at once. The researchers pointed out a chain of 27 rearrangements that sliced and diced six chromosomes and included a TMPRSS2-ERG fusion as well as a disruptive rearrangement of SMAD4.

They also examined the order in which events in chromoplexy chains took place, establishing that the evolution of prostate tumors begins with certain key gene losses or fusions that may be driven partially by chromoplexy. By combining estimate of tumor purity and clonal status — reasoning that clonal alterations had to occur before subclonal ones — the researchers traced the order of events in the tumors.

Following those original changes that appear to affect epithelial differentiation, mutations in CDKN1B or TP53 accumulated, and those changes may lead to further genomic instability, growth, and avoidance of cell death.

"[T]hese results imply that prostate carcinogenesis favors the dysregulation of cancer genes in defined sequences, as has been suggested by studies of developing tumors in colon cancer," the investigators wrote. Such structural changes, the investigators noted, also appeared to be linked to worse histological grade of the tumor.

While the researchers cautioned that their model needs to be further validated, they suggested that this process of chromoplexy and punctuated equilibrium may be common to other tumor types and may inform how patients are treated. "Information about what alterations are common, and which aren't, will most likely help guide us in terms of cancer drug use and patient response," Demichelis said.