Paired exome analysis of Barrett's esophagus and adenocarcinoma

Stachler, Matthew D.; Taylor-Weiner, Amaro; Peng, Shouyong; McKenna, Aaron; Agoston, Agoston T.; Odze, Robert D.; Davison, Jon M.; Nason, Katie S.; Loda, Massimo; Leshchiner, Ignaty; Stewart, Chip; Stojanov, Petar; Seepo, Sara; Lawrence, Michael S.; Ferrer-Torres, Daysha; Lin, Jules; Chang, Andrew C.; Gabriel, Stacey; Lander, Eric S.; Beer, David G.; Getz, Gad; Carter, Scott L.; Bass, Adam J.

doi:10.1038/ng.3343

Cited by 331 publications

(427 citation statements)

References 64 publications

Supporting

Mentioning

381

Contrasting

Unclassified

Order By: Relevance

“…Next, we focused our analysis on recurrently mutated SNPs in EAC (9,28,40). In concordance with previous studies (9), we observed a high percentage (50%) of EAC patients with missense mutation in TP53, whereas no TP53 mutation was detected in NDBE or LGD (Fig.…”

Section: Long Noncoding Rnas Show Characteristic Differential Expresssupporting

confidence: 87%

See 1 more Smart Citation

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

Mååg

Fisher

Levert-Mignon³

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

Esophageal adenocarcinoma (EAC) has one of the fastest increases in incidence of any cancer, along with poor five-year survival rates. Barrett's esophagus (BE) is the main risk factor for EAC; however, the mechanisms driving EAC development remain poorly understood. Here, transcriptomic profiling was performed using RNA-sequencing (RNA-seq) on premalignant and malignant Barrett's tissues to better understand this disease. Machine-learning and network analysis methods were applied to discover novel driver genes for EAC development. Identified gene expression signatures for the distinction of EAC from BE were validated in separate datasets. An extensive analysis of the noncoding RNA (ncRNA) landscape was performed to determine the involvement of novel transcriptomic elements in Barrett's disease and EAC. Finally, transcriptomic mutational investigation of genes that are recurrently mutated in EAC was performed. Through these approaches, novel driver genes were discovered for EAC, which involved key cell cycle and DNA repair genes, such as BRCA1 and PRKDC. A novel 4-gene signature (CTSL, COL17A1, KLF4, and E2F3) was identified, externally validated, and shown to provide excellent distinction of EAC from BE. Furthermore, expression changes were observed in 685 long noncoding RNAs (lncRNA) and a systematic dysregulation of repeat elements across different stages of Barrett's disease, with wide-ranging downregulation of Alu elements in EAC. Mutational investigation revealed distinct pathways activated between EAC tissues with or without TP53 mutations compared with Barrett's disease. In summary, transcriptome sequencing revealed altered expression of numerous novel elements, processes, and networks in EAC and premalignant BE.Implications: This study identified opportunities to improve early detection and treatment of patients with BE and esophageal adenocarcinoma. Mol Cancer Res; 15(11); 1558-69. Ó2017 AACR.

show abstract

Section: Long Noncoding Rnas Show Characteristic Differential Expresssupporting

confidence: 87%

“…5D). a-Satellites, found in the centromere regions of all chromosomes, have been linked to aneuploidy, a well-known feature of EAC (39,40). In light of these observations, we investigated centromere protein (CENP) expression.…”

Section: Long Noncoding Rnas Show Characteristic Differential Expressmentioning

confidence: 99%

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

Mååg

Fisher

Levert-Mignon³

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…15 Copy number change is a strong predictor of progression and changes dramatically in the transition to invasive disease. 10,16,17 Due to the infeasibility, expense and low sensitivity of performing cell cycle analysis or SNP arrays on FFPE Cytosponge material, we selected immunohistochemical expression of Aurora kinase A (AurKA) as a surrogate aneuploidy marker. 18 AurKA expression has also been shown to be significantly upregulated in Barrett's with HGD and OAC compared to non-dysplastic.…”

Section: Introductionmentioning

confidence: 99%

Risk stratification of Barrett's oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study

Ross-Innes

Chettouh

Achilleos

et al. 2017

The Lancet Gastroenterology & Hepatology

View full text Add to dashboard Cite

show abstract

“…Exome sequencing, data processing, and mutation and somatic copy-number aberration analysis were performed, as previously described (43)(44)(45)(46)(47)(48). The ABSOLUTE computational algorithm was performed to evaluate tumor ploidy and to establish evolutionary relationship of the primary and metastatic disease as detailed in Supplementary Methods (49). To confirm that the discrepant mutations were actually absent in the paired sample, samples with discrepant mutations by whole-exome sequencing in genes present in an established targeted gene panel consisting of all exons of 243 genes commonly mutated in GEA (Supplementary Table S1) were resequenced using the targeted panel to a mean target coverage of 242.6×.…”

Section: Cohort 1: Whole-exome Sequencing Of Synchronous Primary Gastmentioning

confidence: 99%

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

et al. 2018

View full text Add to dashboard Cite

Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited effi cacy. A potential reason for the failure of such therapies is that genomic profi ling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, fi nding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed signifi cant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplifi cation profi les commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifi cations not detected in PT sampling. Lastly, we profi led paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profi ling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profi ling to enhance selection of therapy. SIGNIFICANCE:We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profi ling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1);[37][38][39][40][41][42][43][44][45][46][47][48]

show abstract

Paired exome analysis of Barrett's esophagus and adenocarcinoma

Cited by 331 publications

References 64 publications

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

Risk stratification of Barrett's oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

Contact Info

Product

Resources

About