Tag: Cancer Evolution

Evolution of Breast Cancer Mets

[] [Cell]

Genomic Evolution of Breast Cancer Metastasis and Relapse

“We sequenced whole genomes or a panel of 365 genes on 299 samples from 170 patients with locally relapsed or metastatic breast cancer. Several lines of analysis indicate that clones seeding metastasis or relapse disseminate late from primary tumors, but continue to acquire mutations, mostly accessing the same mutational processes active in the primary tumor. Most distant metastases acquired driver mutations not seen in the primary tumor, drawing from a wider repertoire of cancer genes than early drivers. ” “In primary breast cancer, ER-positive and triple-negative tumors show rather distinct combinations of driver mutations, with PIK3CA, GATA3, and MAPK-pathway mutations characterizing the former and TP53 and copy number alterations the latter. When studying relapse and metastasis samples, however, we found that the genomic differences between triple-negative and ER-positive cancers became more blurred: TP53 mutations were seen in 40%–50% of relapsed ER-positive cases; and PIK3CA, GATA3, CDH1, and MAP3K1 all increased several-fold in relapsed ER-negative cancers.” Work from Peter Campbell.




[PMID: 28756993] [Cell]

Conditional Selection of Genomic Alterations Dictates Cancer Evolution and Oncogenic Dependencies

“Cancer genome profiling has revealed that specific events are more or less likely to be co-selected, suggesting that the selection of one event depends on the others. However, the nature of these evolutionary dependencies and their impact remain unclear. Here, we designed SELECT, an algorithmic approach to systematically identify evolutionary dependencies from alteration patterns. By analyzing 6,456 genomes from multiple tumor types, we constructed a map of oncogenic dependencies associated with cellular pathways, transcriptional readouts, and therapeutic response. Finally, modeling of cancer evolution shows that alteration dependencies emerge only under conditional selection. “

CNA Evolution from Primary to CTCs

[PMID: 28487279] [Genome Research]

Single-cell sequencing deciphers a convergent evolution of copy number alterations from primary to circulating tumor cells

“Here, we studied genomic alterations in single primary tumor cells and circulating tumor cells (CTCs) from the same patient. Single-nucleotide variants (SNVs) in single cells from both samples occurred sporadically, whereas CNAs among primary tumor cells emerged accumulatively rather than abruptly, converging toward the CNA in CTCs. Focal CNAs affecting the MYC gene and the PTEN gene were observed only in a minor portion of primary tumor cells but were present in all CTCs, suggesting a strong selection toward metastasis. Single-cell structural variant (SV) analyses revealed a two-step mechanism, a complex rearrangement followed by gene amplification, for the simultaneous formation of anomalous CNAs in multiple chromosome regions.”