Gene Set Enrichment Analysis Identifies Ovarian Tumor Field Defect
J Cuff, AH Beck, TA Longacre. Stanford University, Stanford, CA
Background: Ovarian endometrioid and clear cell carcinoma are associated with endometriosis. A step-wise transformation of a specific precursor lesion has been proposed for clear cell carcinoma, while a possible field defect has been postulated for endometrioid carcinoma, whereby neoplastic progression is distributed throughout the extended mullerian system. We utilized gene set enrichment analysis to determine whether unique patterns of gene expression in ovarian clear cell and endometrioid carcinomas are distinct with regard to endometriois, an acknowledged common precursor lesion.
Design: We pursued a two step bioinformatic approach utilizing publicly available gene expression data. Significance analysis of Microarray's (SAM) was used to construct an endometriosis gene signature by comparing expression array data (GSE7305) from endometriosis (n=10) and cycling eutopic endometrium (n=10). SAM was implemented in R where ∼1000 probes were deemed to be significantly different between the two groups (delta level =5; false discovery rate of zero expected at this level of significance). The second step utilized a data set of stage I ovarian cancers (GSE8841); analysis was restricted to the subset of clear cell and endometrioid carcinomas (n=35). Gene Set Enrichment Analysis (GSEA; Broad institute) was performed to determine if differences in gene expression between clear cell and endometrioid carcinomas differ in a coordinated fashion with respect to the previously defined background/stromal gene expression of endometriosis.
Results: A set of 36 genes was upregulated in endometriosis and significantly enriched in endometrioid but not clear cell carcinoma. Gene annotation revealed several known oncogenes, genes encoding tyrosine kinases, and genes associated with neoplasia inducing translocations. These genes are suspect candidates in the neoplastic transformation of a common precursor lesion into distinct tumor types.
Conclusions: This data provides molecular genetic support for the notion that a field defect with a unique set of genetic changes is operative in ovarian endometrioid but not clear cell tumors. Endometriosis may presage ovarian endometrioid and clear cell carcinoma, however different genetic changes likely participate in divergent morphologic and clinical phenotypes.
Category: Pan-genomic/Pan-proteomic Approaches to Diseases
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 251, Monday Morning