Reconstructing Breakage Fusion Bridge Architectures Using Noisy Copy Numbers

Abstract

The Breakage Fusion Bridge (BFB) process is a key marker for genomic instability, producing highly rearranged genomes in relatively small numbers of cell cycles. While the process itself was observed during the late 1930s, little is known about the extent of BFB in tumor genome evolution. Moreover, BFB can dramatically increase copy numbers of chromosomal segments, which in turn hardens the tasks of both reference-assisted and ab initio genome assembly. Based on available data such as Next Generation Sequencing (NGS) and Array Comparative Genomic Hybridization (aCGH) data, we show here how BFB evidence may be identified, and how to enumerate all possible evolutions of the process with respect to observed data. Specifically, we describe practical algorithms that, given a chromosomal arm segmentation and noisy segment copy number estimates, produce all segment count vectors supported by the data that can be produced by BFB, and all corresponding BFB architectures. This extends the scope of analyses described in our previous work, which produced a single count vector and architecture per instance. We apply these analyses to a comprehensive human cancer dataset, demonstrate the effectiveness and efficiency of the computation, and suggest methods for further assertions of candidate BFB samples. Source code of our tool can be found online.

AmpliconReconstructor: Integrated analysis of NGS and optical mapping resolves the complex structures of focal amplifications in cancer

“…In subsequent cellular division, the asymmetric breaking of the fused dicentric chromosome structure results in one daughter cell having an increased copy number of pieces of the previously fused chromosome. The structure of various BFBs have been analyzed using cytogenetic techniques 14 and also by computational models that predict a BFB mechanism based on copy number counts 38, 39 . Both methods are imprecise, to a degree, and may fail to capture the fine structure of the BFB or handle imprecise copy number counts and/or additional structural variants (SVs) inside the BFB.…”

Reconstructing and characterizing focal amplifications in cancer using AmpliconArchitect

“…While these include small nucleotide changes, and chromosomal aneuploidies, focal amplifications of smaller regions are also a prominent signature in a large proportion of human cancers 1 . Focally amplified regions are found to be hotspots for genomic rearrangements, which can include the juxtaposition of segments of DNA from distinct chromosomal loci, into a single amplified region [2][3][4][5][6][7][8] . While common, these types of focal gene amplification present a mechanistic challenge --how do multiple regions from one or more chromosomes rearrange together in cancer?…”