Unknown,Transcriptomics,Genomics,Proteomics

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Identification of a gene expression signature for survival prediction in type I endometrial carcinoma

ABSTRACT: Endometrial cancer is the most common malignancy of the female reproductive tract. In many cases the prognosis is favourable, but 22% of affected women die from the disease. We aimed to study potential differences in gene expression between endometrioid adenocarcinomas from survivors (5-year survival) and non-survivors. Forty-five patients were included in the investigation, of which 21 were survivors and 24 were non-survivors. The tumours were analysed with genome-wide expression array analysis, represented by 13526 genes. Distinct differences in gene expression were found between the groups. A t-test established that a set of 218 genes were significantly differentially expressed (P < 0.001) between the two survival groups, and in a cross validation test 40 of the 45 (89%) tumours were classified correctly. The 218 differentially expressed genes were subjected to hierachical clustering analysis which yielded two clusters both exhibiting over 80% homogeneity with respect to survival. When the additional constraint of fold change (FC>2) was added the hierachical clustering yielded similar results. Tumour cDNA from both groups (survivors vs. non-survivors) were hybridised together with the same reference, and we were able to calculate the relative expression level value for the sample Stage I tumours are expected to have a favourable prognosis. However, in our tumour material there were six non-survivors with stage I tumours. Five out of six stage I non-survivors clustered in the non-survival fraction. Our findings suggest that a subgroup of early stage endometroid adenocarcinomas can be correctly classified as potentially aggressive by using molecular biology in combination with conventional markers, thereby providing a tool for a more accurate classification and risk evaluation of the individual patient.

ORGANISM(S): Homo sapiens

SUBMITTER: Kristina Levan

PROVIDER: E-GEOD-21882 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. Some of these patients may become long-term survivors. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression to trastuzumab. 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Sixty-five per cent of tumours were poorly differentiated ductal carcinomas and hormonal receptors were present in 47%. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median progression-free survival was 10.6 years after the diagnosis of metastatic disease. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival . Gene ontology analysis demonstrated that genes involved in HIF activation, EGF receptor signalling pathway, PI3 kinase pathway, apoptosis signalling pathway and p53 pathway significantly correlated with response. The PI3K pathway was the most strongly associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. These findings support that trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression to trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy. 53 FFPE samples, which passed the RNA quality control criteria, were analyzed (45 primary tumours and 8 metastases). Among these 53 samples, 35 samples corresponded to long-term responders and 18 to the control group.

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Identification of a gene expression signature for survival prediction in type I endometrial carcinoma

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