In the outgoing phase of this project, we aimed to characterize the landscape of complex rearrangements in human cancers using whole-genome sequencing data from >2,600 patients
collected under the auspices of the International Cancer Genome Consortium (ICGC) and the Pan-Cancer Analysis of Whole Genomes project (PCAWG).
Complex rearrangements consist of massive alterations of chromosomes that often lead to the rearrangement of large DNA segments, which can lead to e.g. gene fusions, amplification of oncogenes or loss of tumor suppressors.
This work has been performed at the laboratory of Prof. Peter Park at Harvard Medical School and as part of the Structural Variation Working Group of PCAWG.
Among the diverse types of complex rearrangements, we focused in particular on the analysis of chromothripsis patterns.
Chromothripsis is a recently discovered mutational process characterized by massive genomic rearrangements, which are often generated in a single catastrophic event and can affect from one to multiple chromosomes.
In contrast to the traditional view of tumorigenesis as a gradual process of mutation accumulation, chromothripsis represents a mechanism for the rapid acquisition of hundreds of rearrangements in few cell divisions.
Although initial studies of human tumors using low-resolution array data estimated a frequency of chromothripsis of 3-5%, our analysis has revealed that chromothripsis is pervasive in human cancers,
with a frequency of >50% in several cancer types. We have found that about 50% of the events we detect show the canonical pattern of chromothripsis, characterized by random rejoining of DNA fragments, copy number oscillations between two states and interspersed loss of heterozygosity. However, the remaining cases show more complex rearrangement patterns, usually colocalized with other complex alterations, such as secondary massive amplification of oncogenes, indicating that multiple types of complex rearrangements often coexist in cancer cells. Analysis of cancer-related genes in tumors harboring chromothripsis events revealed that chromothripsis contributes to oncogene amplification, as well as to inactivation of tumor suppressor genes, such as mismatch-repair related genes. Overall, our findings show that chromothripsis is a major process driving genome evolution in human cancer.
