📄️ Global Pattern
Genome-wide occurrences of specific structural variants (SVs) may indicate possible DNA repair deficiencies in cancer. For example, inactivation of a homologous recombination gene, such as BRCA1 and BRCA2, leads to chromosomal instability, thereby increasing the likelihood of therapeutic response to PARP inhibition. In Chromoscope, the genomic signature is apparent as hundreds of scattered deletions and duplications with sizes of 1–10 kb are shown in the genome (Fig. 1, left column) and variant views (Fig. 1, right column). In the variant view, the footprint on the copy number profiles is consistent with losses and gains caused by deletions and tandem duplications.
📄️ Biallelic Loss of Tumor suppressor
Chromoscope facilitates the interpretation of clinically-relevant SVs in cancer genomes.
📄️ Pathogenic BRCA Mutations
The BRCA1 and BRCA2 genes have a role in the accurate repair of DNA double-strand breaks through homologous recombination deficiency. A mutational signature of BRCA1/2 loss consists of multiple mutation types (point mutations, indels, structural and copy number variants). The exact mechanisms of how such mutations form in the context of homologous recombination deficiency have not been fully understood.
📄️ Co-amplifications
The amplifications of chromosomes 8 and 11 in breast cancer co-occur. An inspection of these loci with Chromoscope shows that the amplifications are often connected by inter-chromosomal translocations, implicating the derivative chromosome 8/11 as an early event in their formation. The segments of loss-of-heterozygosity (LOH) adjacent to the amplicon loci are consistent with this model of amplicon origin. The visualization highlights commonalities in features of the amplicons across 23 samples, as featured in a recent study on the origin of these amplicons.
📄️ Biallelic ATM Mutations
The ataxia-telangiectasia mutated (ATM) gene is essential in the detection and signaling to repair DNA double-strand breaks. Carriers of germline mutations in ATM are predisposed to cancer, and ATM is also often mutated somatically. In light of new cancer therapies targeting cells with ATM loss, we hypothesized that ATM loss would result in a mutational signature apparent in cancer genomes.
📄️ CCNE1 Amplifications
The CCNE1 gene is commonly amplified in different cancer types, and results in oncogenic stress. Cancers with CCNE1 amplifications often display a characteristic signature of structural variants and are dominated by somatic tandem duplications.
📄️ Biallelic Loss of CDK12
The CDK12 gene is a cyclin-dependent kinase and controls the cell cycle, cell division, and transcription. Cancers with pathogenic CDK12 mutations display chromosomal instability and their genomes are dominated by somatic tandem duplications. The mechanistic connection between the CDK12 loss and chromosomal instability remains unresolved, and uncovering the mechanism might inform new cancer therapies.