The landscape of selection in 551 Esophageal Adenocarcinomas defines genomic biomarkers for the clinic

Frankell, Alex M; Jammula, Sriganesh; Li, Xiaodun; Contino, Gianmarco; Killcoyne, Sarah; Abbas, Sujath; Perner, Juliane; Bower, Lawrence; Devonshire, Ginny; Ococks, Emma; Grehan, Nicola; Mok, James; O’Donovan, Maria; MacRae, Shona; Eldridge, Mathew; Tavaré, Simon; Fitzgerald, Rebecca

doi:10.1101/310029

Cited by 61 publications

(139 citation statements)

References 62 publications

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“…The amplified genes can be grouped into functional biological pathways with the RAS-ERK signalling pathway (e.g. ERBB2; EGFR; KRAS) and GATA transcription factors (GATA4; GATA6) being the most common (Frankell et al, 2019; Lin et al, 2012; The Cancer Genome Atlas Research Network et al, 2017). The morphology of BO differs from the oesophageal epithelia by the presence of a columnar epithelium and secretory goblet cells, rather than squamous epithelium (reviewed in Spechler and Souza, 2014).…”

Section: Introductionmentioning

confidence: 99%

Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

Rogerson

Ogden

Britton

et al. 2020

Preprint

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Oesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barrett's oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC. similar GO terms to those enriched in genes upregulated in OAC compared to BO ( Fig. 3F).GSEA also identified the same gene set terms: "G2M checkpoint" and "E2F1 targets" (Fig. 3G).Next we asked whether these genes are directly regulated by KLF5, and carried out ChIPseq for KLF5 in OE19 cells. Anti-KLF5 antibodies precipitated KLF5 ( Supplementary Fig. 3I) and biological replicates were highly reproducible ( Supplementary Fig. 3J). Therefore, we took the overlap of peaks between biological replicates forward for downstream analyses, resulting in 13,542 peaks ( Supplementary Fig. 3K; Supplementary Table S5). These peaks are highly enriched in the KLF5 motif, demonstrating the validity of the dataset, and also in AP1(FRA1) and GATA (GATA6) motifs, which we have previously revealed in genome wide studies as implicated in OAC (Britton et al., 2017; Rogerson et al., 2019) ( Supplementary Fig. 3L). Focussing on the 97 genes that are upregulated in OAC and also downregulated after KLF5 depletion, 97% have a KLF5 ChIP-seq peak within 0.5 Mb of the TSS and the median distance between a KLF5 ChIP-seq peak and the TSS was 15,604 bp ( Supplementary Fig. 3M). This is indicative of direct regulation by KLF5. An example gene is CDC25B which harbours multiple KLF5 ChIP-seq peaks surrounding its locus (Fig. 3H).Collectively, these results suggest a direct activator role of KLF5 in controlling cell cycle genes in OAC. The KLF5 cistrome is reconfigured during the progression from BO to OAC.Having determined a role for KLF5 in controlling cell cycle associated gene expression in OAC cells, we sought to determine the mechanism through which KLF5 acquires these functions. We first asked whether KLF5 expression changes in the transition from BO to OAC, however no increase in expression was found (Fig. 4A). An alternative me...

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Section: Introductionmentioning

confidence: 99%

Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

Rogerson

Ogden

Britton

et al. 2020

Preprint

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“…1E, Table S1 (A companion study investigating Barrett's esophagus WGS dataset in detail is currently in preparation). In summary, our analysis included 1,668 WGS samples not currently within the Pan-Cancer Analysis of Whole Genomes (PCAWG) effort, including published studies (Nik-Zainal et al, 2016;Hayward et al, 2017;Baca et al, 2013;Barretina et al, 2012;Frankell et al, 2019), The Cancer Genome Atlas (TCGA, 1017 cases), International Cancer Genome Consortium (ICGC, 876 cases), or Cancer Cell Line Encyclopedia (CCLE, 326 cases) (Barretina et al, 2012;Ghandi et al, 2019). Though the majority of our analyzed samples consisted of primary tumors, 283 out of the 2,833 samples were extracted or derived from metastatic tumors.…”

Section: Introductionmentioning

confidence: 99%

Novel patterns of complex structural variation revealed across thousands of cancer genome graphs

Hadi

Yao

et al. 2019

Preprint

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Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g. deletion, translocation) or complex (e.g. chromothripsis, chromoplexy) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,833 tumor whole genome sequences (WGS), we introduce three complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early replicating regions and superenhancers, and are enriched in breast and ovarian cancers. Rigma comprise "chasms" of low-JCN deletions at late-replicating fragile sites in esophageal and other gastrointestinal (GI) adenocarcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold back inversions that are enriched in acral but not cutaneous melanoma and associated with a previously uncharacterized mutational process of non-APOBEC kataegis. Clustering of tumors according to genome graph-derived features identifies subgroups associated with DNA repair defects and poor prognosis. Cancer genomics | Structural variation | DNA rearrangements | Mutational Processes | Genome graphs | Copy number alterationsCorrespondence: mski@mskilab.org K. Hadi, X.Yao, J. Behr et al. | bioRχiv | November 12, 2019 | 1-8

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“…One reason for the poor prognosis is the lack of tailored therapies due to the relative paucity of molecular knowledge compared to other cancers. We are beginning to understand the molecular mechanisms underpinning this disease, chiefly through genomic sequencing studies, which have revealed multiple genes that are recurrently mutated in OAC (Dulak et al 2013;Weaver et al, 2014;Ross-Innes et al, 2015;Frankell et al, 2018). However, with the exception of TP53, the overall incidence of mutations in individual genes is low.…”

Section: Introductionmentioning

confidence: 99%

Identification of a primitive intestinal transcription factor network shared between oesophageal adenocarcinoma and its pre-cancerous precursor state

Rogerson

Britton

Withey

et al. 2018

Preprint

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Running title: Barrett's oesophagus and OAC share a primitive intestinal transcription factor network. AbstractOesophageal adenocarcinoma (OAC) is one of the most frequent causes of cancer deaths and yet compared to other common cancers, we know relatively little about the molecular composition of this tumour type. To further our understanding of this cancer we have used open chromatin profiling to decipher the transcriptional regulatory networks that are operational in OAC. We have uncovered a transcription factor network that is usually found in primitive intestinal cells during embryonic development, centred on HNF4A and GATA6. These transcription factors work together to control the OAC transcriptome. Importantly, we show that this network is activated in Barrett's oesophagus, the putative precursor state to OAC thereby providing novel molecular evidence in support of stepwise malignant transition. Furthermore, we show that HNF4A alone, is sufficient to drive chromatin opening and activation of a Barrett's-like chromatin signature when expressed in normal human epithelial cells. Collectively, these data provide a new way to categorise OAC at a genome scale and implicate HNF4A activation as a potential pivotal event in regulating its malignant transition from healthy cells. Results Identification of a network of transcription factors active in OACPreviously we used ATAC-seq to profile the open chromatin landscape of OAC cell lines and identified AP1 as an important transcription factor family in controlling the transcriptional networks in OAC . To further interrogate the transcriptional networks operating in OAC, we decided to take an alternative approach, starting with clearly defined open chromatin datasets from OAC patient samples rather than a diverse set of OAC-derived cell lines. We previously validated our cell line-derived results by profiling the open chromatin of six patient-derived biopsies but this revealed two distinct subclusters of OAC samples based on their open chromatin landscapes; one that clustered with normal samples and one that was unique . We revisited this issue by performing subclustering by PCA analysis following the addition of an additional paired normal and OAC dataset and again we observed a clear partitioning of samples ( Supplementary Fig. S1A). We therefore re-focussed our attention on the four OAC samples which are clearly distinct from the normal samples (T_002, T_003, T_005, T_006; Supplementary Fig. S1A).To derive a unified dataset of open chromatin regions in oesophageal-derived tissue, we combined all the ATAC-seq data from three normal oesophageal tissue samples (matched with T_003, T_005 and T_006) and these four OAC samples and recalled the open accessible chromatin regions from this combined data. We selected the top 50,000 open regions ( Supplementary Table S1A) and found that these were roughly equally divided between promoter-proximal, intragenic and intergenic regions (Fig. 1A). PCA analysis based on these peaks confirmed the distinct clustering of the normal an...

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The landscape of selection in 551 Esophageal Adenocarcinomas defines genomic biomarkers for the clinic

Cited by 61 publications

References 62 publications

Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

Novel patterns of complex structural variation revealed across thousands of cancer genome graphs

Identification of a primitive intestinal transcription factor network shared between oesophageal adenocarcinoma and its pre-cancerous precursor state

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