Exploring tumor evolution from primary to metastatic cancers: a multi-omics profile

Abstract

Colorectal cancer (CRC) remains a major public health issue. The evolutionary events that cause colorectal localized tumors to progress to metastasis remain mostly unknown. Chromosomal alterations seem to be important in the chain of events that leads to the development of CRC that cooperate with mutations of well-described tumor-associated mutations such as APC, KRAS and p53. Furthermore, KRAS mutations in CRC have generally been found to be mutually exclusive with BRAF mutations. In CRCs with the chromosomally unstable phenotype, BRAF mutations are rarely observed, they are much more frequent in CRCs displaying the microsatellite instability phenotype. Also, it remains unclear how exactly aneuploidy shapes the transcriptome of cancer cells and if, and then why, cancer cells require aneuploidy-specific deregulated transcriptional networks. In that sense, we aim to investigate potential relationships between BRAF mutations, the degree of DNA ploidy and tumor stage in human CRC using multi-region genome sequencing and organoids of primary and metastatic samples. With the understanding of how these tumors evolve - and which subclones are responsible for the emerge of metastasis - we hope to provide better therapeutical options for cancers harboring characteristics of poor prognosis. (AU)