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Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer (RNA-Seq)

ABSTRACT: Metastasis is the cause of death for 90% of cancer patients, but little is known about how cancer cells adapt to and colonize new tissue environments. Using clinical samples and primary/metastatic cell lines, we found metastatic colorectal cancer (CRC) cells lose their colon-specific gene transcription program and gain a liver-specific gene transcription program as they metastasize in the liver. We revealed this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical and super-enhancers. Further, we identified FOXA2, a liver-specific transcription factor, plays a key role in this transcription reprogramming and the colonization of metastatic CRC cells in the liver. Notably, this transcription reprogramming is also observed in multiple cancer types. Our data demonstrate that epigenetically reprogrammed tissue-specific transcription promotes metastasis and should be targeted therapeutically.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106920 | GEO | 2020/06/30

REPOSITORIES: GEO

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Project description:Background: Liver metastasis is the major cause of death following a diagnosis of colorectal cancer (CRC) and is a major health burden. Most molecular studies of CRC have profiled primary tumor samples and not the metastasis samples. In this study, we compared the copy number profiles of matched primary and liver metastatic CRC to better understand how the genomic structure of primary CRC differs from the metastasis. This has important implications for whether it is justified to base therapeutic approaches solely on data from the primary tumour. Methods: Paired primary and metastatic tumours from 16 patients and their adjacent normal tissue samples were analyzed using Single-Nucleotide-Polymorphism (SNP) arrays to determine copy number alterations. Nine patients had a synchronous liver metastasis at the time of CRC diagnosis and 7 patients developed a liver metastasis metachronously. Genome-wide chromosomal copy number alterations were assessed, with particular attention to 189 genes known to be somatically altered in CRC and 25 genes that are clinically actionable in CRC. These data were analyzed with respect to the timing of primary and metastatic tissue resection and with exposure to chemotherapy. Results: The genomic divergence with the whole genome duplication correction applied the average percent copy number discordance across all pairs of samples was 22.02%. The pairs of tumour samples collected prior to treatment revealed a significantly higher copy number differences compared to previously treated liver metastasis samples (P=0.024). However, loss of heterozygosity (LOH) acquired in metastasis was significantly higher in previously treated liver metastasis samples compared to treatment naïve liver metastasis samples (P= 0.0064) and which included where KRAS mutation was present in the primary cancers but was not detectable in the metastatic sample following chemotherapy. With regard to 25 genes that are clinically actionable in CRC, amplification of the genes ERBB2, FGFR1, CDK8 or PIK3CA was observed in the metastatic tissue of 4 patients but not in the matched primary CRC. In these cases, knowledge of these metastatic specific alterations could have informed therapeutic decision making and may have improved patient outcome. Conclusion: Intra-patient genomic discrepancies observed between primary and metastatic tissue

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Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer (RNA-Seq)

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