A 4-Gene Signature Predicts Survival of Patients With Resected Adenocarcinoma of the Esophagus, Junction, and Gastric Cardia

Peters, Christopher J.; Rees, John; Hardwick, Richard; Hardwick, James S.; Vowler, Sarah L.; Ong, Chin-Ann Johnny; Zhang, Chunsheng; Save, Vicki; O’Donovan, Maria; Rassl, Doris M.; Alderson, Derek; Caldas, Carlos; Fitzgerald, Rebecca C.

doi:10.1053/j.gastro.2010.05.080

Cited by 138 publications

(132 citation statements)

References 38 publications

Supporting

Mentioning

125

Contrasting

Order By: Relevance

“…28 SIRT2 expression was already used in a 4-gene molecular prognostic signature in esophageal and junctional adenocarcinoma, and similar to our study, a high expression of SIRT2 was associated with good prognosis. 29 These results are consistent with the fact that SIRT2 can normally promote cell death, and its overexpression can also mediate a delay in cellular proliferation. 30 In addition, SIRT2 has been shown to suppress tumorigenesis by deacetylating co-activators of the anaphase-promoting complex/ cyclosome activity.…”

Section: Discussionsupporting

confidence: 84%

HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance

et al. 2012

View full text Add to dashboard Cite

Histone deacetylases (HDACs) play a crucial role in chromatin structure and, consequently, gene expression. Their deregulation has been reported in various cancers. We performed a complete and comprehensive study of the expression of 18 HDACs (including Sirtuin; SIRT) by real-time PCR in a cohort of 200 chronic lymphocytic leukemia (CLL) patients with a median follow-up of 77 mo, and compared it with the results obtained from normal B cells. We also compared HDAC expression at diagnosis and after relapse. We observed significant deregulation (mostly upregulation) of HDACs in CLL. In terms of clinical significance, only HDAC6 was significantly correlated with treatment-free survival (TFS), whereas HDAC3 and SIRT2, 3 and 6 were correlated with overall survival (OS). A multivariate Cox regression stepwise analysis indicated that HDAC6, 7 and 10 and SIRT3 were TFS independent predictors. Interestingly, poor prognosis was associated with an overexpression of HDAC7 and 10 but an underexpression of HDAC6 and SIRT3. Therefore, these factors were combined in a TFS score: patients with a score of 0-1-2, 3 and 4 had a median TFS of 107, 57 and 26 mo, respectively (HR = 4.03, p < 0.0001). For OS, SIRT5 and 6 allowed stratification into 3 groups, with a median OS of > 360, 237 and 94 mo (HR = 6.38, p < 0.0001). However, we could not find statistical differences in HDAC expression after relapse. These results, validated by a 5-fold cross-validation, highlight the complex impact of HDAC expression in CLL clinical course.

show abstract

Section: Discussionsupporting

confidence: 84%

HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Tissue microarrays (TMAs) of oesophageal and gastric samples (n=434) were generated21 (demographics in table S1 for samples in the TMA). An expert gastrointestinal pathologist selected three separate cores for each case.…”

Section: Methodsmentioning

confidence: 99%

A systematic approach to therapeutic target selection in oesophago-gastric cancer

Paterson

Shannon

Lao‐Sirieix

et al. 2012

Gut

Self Cite

View full text Add to dashboard Cite

Objective The success of personalised therapy depends on identification and inhibition of the oncogene(s) on which that tumour is dependent. We aimed to determine whether a receptor tyrosine kinase (RTK) array could be used to select the most effective therapeutic strategies in molecularly heterogeneous oesophago-gastric adenocarcinomas. Design Gene expression profiling from oesophagogastric tumours (n=75) and preinvasive stages (n=57) identified the active signalling pathways, which was confirmed using immunohistochemistry (n=434). RTK arrays on a cell line panel (n=14) determined therapeutic targets for in vitro cytotoxic testing. Feasibility of this personalised approach was tested in tumour samples (n=46). Results MAPK was the most frequently activated pathway (32/75 samples (42.7%)) with progressive enrichment in preinvasive disease stages ( p<0.05) and ERK phosphorylation in 148/434 (34.3%) independent samples. Cell lines displayed a range of RTK activation profiles. When no RTKs were activated, tyrosine kinase inhibitors (TKIs) and a Mek inhibitor were not useful (MKN1). In lines with a dominant phosphorylated RTK (OE19, MKN45 and KATOIII), selection of this TKI or Mek in nM concentrations induced cytotoxicity and inhibited Erk and Akt phosphorylation. In cells lines with complex activation profiles (HSC39 and OE33), a combination of TKIs or Mek inhibition (in nM concentrations) was necessary for cytotoxicity and inhibition of Erk and Akt phosphorylation. Human tumours demonstrated diverse activation profiles and 65% of cases had two or more active RTKs. Conclusions The MAPK pathway is commonly activated in oesophago-gastric cancer following activation of a variety of RTKs. Molecular phenotyping can inform a rational choice of targeted therapy.

show abstract

“…Gene expression microarray analysis of the RNA from these tumours was performed previously (GEO accession number GSE19417) 18. In brief, RNA was extracted from ten 30 μm sections of each tumour using Trizol according to the manufacturer's instructions (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…TMAs of samples from external datasets (n=371) were available resulting from collaboration with the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) study group 18. IHC was performed on a Bond System (Leica Microsystems (UK) Ltd, Milton Keynes, UK) according to manufacturer's recommendations after confirming antibody specificities by western blotting (data not shown), followed by optimisation on positive control cell blocks and oesophageal tissue sections.…”

Section: Methodsmentioning

confidence: 99%

Integrative analysis of array-comparative genomic hybridisation and matched gene expression profiling data reveals novel genes with prognostic significance in oesophageal adenocarcinoma

Goh

Rees

Paterson

et al. 2011

Gut

View full text Add to dashboard Cite

show abstract

A 4-Gene Signature Predicts Survival of Patients With Resected Adenocarcinoma of the Esophagus, Junction, and Gastric Cardia

Abstract: This study has generated a clinically applicable prognostic gene signature that independently predicts survival in an external validation cohort and may inform management decisions.

Cited by 138 publications

References 38 publications

HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance

HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance

A systematic approach to therapeutic target selection in oesophago-gastric cancer

Integrative analysis of array-comparative genomic hybridisation and matched gene expression profiling data reveals novel genes with prognostic significance in oesophageal adenocarcinoma

Contact Info

Product

Resources

About