Richardson, A. L. | Search bioRxiv

bioRxiv2021

Spatial genomics maps the structure, character and evolution of cancer clones

Subclonality is a universal feature of cancers yet how clones grow, are spatially organised, differ phenotypically or influence clinical outcome is unclear. To address this, we developed base specific in situ sequencing (BaSISS). In fixed tissues, transcripts harbouring clone-defining mutations are detected, converted into quantitative clone maps and characterised through multi-layered data integration. Applied to 8 samples from key stages of breast cancer progression BaSISS localised 1.42 million genotype informative transcripts across 4.9cm2 of tissue. Microscopic clonal topographies are shaped by resident tissue architectures. Distinct transcriptional, histological and immunological features distinguish coexistent genetic clones. Spatial lineage tracing temporally orders clone features associated with the emergence of aggressive clinical traits. These results highlight the pivotal role of spatial genomics in deciphering the mechanisms underlying cancer progression.

cancer biology↗

bioRxiv2018

Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation

Global loss of DNA methylation and CpG island (CGI) hypermethylation are regarded as key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which can extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. Using whole genome bisulfite sequencing (WGBS) of breast cancers, we comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of variation in DNA methylation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). However, significant repression effects on cancer-genes are negligible as tumor suppressor genes are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin of different cancers and may represent tissue-specific silent regions of the genome, which tolerate instability at the epigenetic, transcriptomic and genetic level.

cancer biology↗