Cancer geneticists have identified 21 clusters of complex chromosomal rearrangements in breast cancers that contain both known oncogenes and potential new driver loci.
A systematic analysis of chromosomal rearrangements in tissues from 560 patients with breast cancer identified 21 “hotspots,” some of which contain known oncogene chromosomal loci, and others of which contain genes not typically associated with breast cancer, reported Serena Nik-Zainal, PhD, of the University of Cambridge, England, and her colleagues.
“Detailed analysis of rearrangements at these hotspots highlights chromosomal aberrations likely driven by selection, and reveal underlying mutational processes,” they wrote in a study published online in Annals of Oncology.
The investigators sought insight into mutational mechanisms of gene amplifications by examining clustered rearrangements – somatic breakpoints occurring in high densities – in individual patients.
To see whether these rearrangements were associated with breast cancer, they identified the aforementioned chromosomal hotspots where clustered rearrangements were seen in samples from different patients.
They identified 624 cluster rearrangements in the 560 breast cancer genomes, including 17,247 within-chromosome rearrangements, and 6,509 between-chromosome translocations.
Of the 560 samples, 372 had at least one rearrangement cluster, with the frequency of clusters similar between some breast cancer types. For example, there were 0.96 rearrangements clusters per sample from patients with triple negative breast cancers, and 1.00 per sample from women with estrogen receptor–positive tumors.
“To identify loci where clusters of rearrangements recur across multiple independent tumor samples, we pooled all breakpoints in the ‘clustered’ category and sorted them according to position in the reference genome,” the investigators explained.
They used a Piecewise-Constant-Fitting algorithm to identify genome sequences where there were short inter-mutation distances between rearrangement clusters, suggesting the presence of hotspots.
In the 21 hotspots they identified, they found, as expected, common driver amplification regions (e.g., CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC), but also several hotspots near oncogenes that are not typically associated with breast cancer.
Notably, they saw simultaneous amplification of regions on chromosomes 8 and 11 (chr8:ZNF703/FGFR1 and chr11:CCND1). Amplification of these regions are frequent in estrogen receptor–positive breast cancers. The investigators propose a pathogenic model in which a chromosome 8 to chromosome 11 translocation is an early, critical event leading to breast tumor development.
“Clustered rearrangements are common in breast cancer genomes, and often associated with gene amplifications that drive oncogenesis. Understanding the process of amplicon formation, an example of which we present here for the chr8:ZNF703/FGFR1 and chr11:CCND1 co-amplifications, will be important for our understanding of the origins of a subset of breast cancers,” they concluded.
The study was supported by an award from the Wellcome Trust. Dr. Nik-Zainal and coauthor Dominik Glodzik are inventors on several patent applications. All remaining authors declared no conflicts of interest.
SOURCE: Glodzik D et al. Ann Oncol. 2018 Sept 25. doi: 10.1093/annonc/mdy404.
