Punctuated Evolution of Prostate Cancer Genomes

Abstract

SUMMARY The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term “chromoplexy”, frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events along which chromoplexy may drive prostate carcinogenesis.

Identification of complex genomic rearrangements in cancers using CouGaR

“…3). In the case of prostate cancers, we see that nearly 63% of the samples analyzed have contigs that span three or more chromosomes, very similar to reported numbers (Baca et al 2013). It is of note that we see ∼27% of bladder cancer samples analyzed to have contigs spanning multiple chromosomes.…”

“…Chromoplexy, a phenomenon where complex genomic rearrangements typically involving up to 10 chromosomes is not uncommon, is known to occur extensively in prostate cancers (Baca et al 2013;Zhang et al 2013). We therefore looked at the distribution of contigs that span single, double, or multiple chromosomes For each of the identified contigs, we report their copy count, size, their type, and whether it was also identified by two other approaches.…”

Comprehensive characterization of complex structural variations in cancer by directly comparing genome sequence reads

“…3). In fact, 8 out of the 18 breakpoints appeared to be rejoined reciprocally, as recently described in prostate tumors 16,17 , suggesting an original organization of the chromatin where these regions were physically proximal and somehow interacting. A third translocation identified in the M003 tumor implies the breakage and putative inactivation of ARID2, a gene involved in chromatin remodeling.…”

“…By considering the number of rearrangements identified in this tumor, their distribution and the number of chromosomes involved, we classify this scenario as chromoplexy, a recently described phenomenon that, in contrast to chromothripsis 14 , is characterized by the presence of tens of unclustered chained rearrangements involving two or more chromosomes 16,17 . The high fraction of reciprocal rejoining events found in this tumor, together with the fusion of genes and the disruption of a chromatin remodeler gene, is also in agreement with the results of the chromoplectic events identified in prostate tumors.…”

Cancer evolution and heterogeneity

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This multiregional analysis (MRA) sequencing approach enabled us not only to observe spatial heterogeneity, but also to calculate temporal alterations and eventually disclose the evolution of tumors. There are two types of somatic aberration in a tumor: ubiquitous aberrations (founder mutations, trunk mutations, or clonal mutations) and scattered aberrations (progressor mutations, branch/leaf mutations, or subclonal mutations).…”