Mutational signatures of complex genomic rearrangements in human cancer

Complex genomic rearrangements (CGRs) are common in cancer and are known to form via two aberrant cellular structures-micronuclei and chromatin bridge. However, which mechanism is more relevant to CGR formation in cancer cells and whether there are other undiscovered mechanisms remain open questions. Here, we analyze 2,014 CGRs from 2,428 whole-genome sequenced tumors and deconvolute six CGR signatures based on the topology of CGRs. Through rigorous benchmarking, we show that our CGR signatures are highly accurate and biologically meaningful. Three signatures can be attributed to known biological processes-micronuclei- and chromatin-bridge-induced chromothripsis and extrachromosomal DNA. More than half of the CGRs belong to the remaining three newly discovered signatures. A unique signature (we named "hourglass chromothripsis") with highly localized breakpoints and small amount of DNA loss is abundant in prostate cancer. Through genetic association analysis, we find SPOP as a candidate gene causing hourglass chromothripsis and playing important role in maintaining genome integrity. Our study offers valuable insights into the formation of CGRs.