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Imaging, Genetic Analysis Points to Driver Role for PTEN Loss in Ovarian Cancer

NEW YORK (GenomeWeb) – In a study appearing online last night in Genome Biology, a UK-led team used a combination of imaging and genomic data to characterize a form of ovarian cancer known as high-grade serous ovarian carcinoma.

The researchers reasoned that by tapping into tumor section imaging data, they might be able to dig up previously overlooked genes driving disease formation, since past research has pointed to just a few main ovarian cancer culprits (namely, germline glitches in BRCA1 and BRCA2 or somatic mutations in the TP53 genes). 

The team considered gene expression and other genomic data for hundreds of high-grade serous ovarian carcinoma samples collected for the Cancer Genome Atlas project and other large-scale studies with the added context of tumor section imaging information.

Using this strategy, investigators saw diminished levels of the tumor suppressor gene PTEN in cancerous cells but not in neighboring, normal cells. The work suggests that loss or lower-than-usual expression of PTEN can prompt ovarian cancer development, though co-first author Filipe Correia Martins noted that additional research is necessary to explore potential clinical applications of this ovarian cancer driver.

"The next step is to develop our approach to be able to rapidly identify tumours with low levels of PTEN, so that doctors can pick the best treatments," Martins, a researcher affiliated with the University of Cambridge's Cancer Research UK Cambridge Institute and the National Institute for Health Research Cambridge Biomedical Centre, said in a statement.

Efforts to understand the genetic underpinnings of high-grade serous ovarian carcinoma had previously uncovered mutational similarities between that most common form of ovarian cancer and basal-like breast cancer. Both are prone to somatic alterations involving TP53, authors of the new analysis explained, and both can occur in individuals carrying germline changes to the BRCA1 genes.

Basal-like breast cancer has been linked to other driver events, too, including reduced PTEN levels. And that prompted the team to take a closer look at a possible role for PTEN loss in high-grade serous carcinoma development.

PTEN glitches had been described in a relatively small proportion of high-grade serous carcinoma cases considered by TCGA, the researchers explained. But they suspected that they might find a more widespread role for PTEN by weeding out so-called stromal cells based on gene expression and imaging information.

In 216 TCGA samples of high-grade serous carcinoma, the team's methods successfully distinguished between stromal and cancerous cells in hundreds of images assessed visually and computationally. There, stromal cells tended to show far more robust expression of PTEN than their cancerous counterparts.

The researchers followed up on these findings with a series of experiments that included array-based expression profiling, semi-quantitative immunofluorescence, and/or immunohistochemistry on hundreds more ovarian cancer samples. Again, they found reduced PTEN expression in some high-grade serous carcinomas, particularly those from cases with poor outcomes.

Expression of the gene varied from tumor-to-tumor, Martins and co-authors noted, but the low PTEN profile tended to overlap with tumors classified in the "proliferative" and TCGA sub-group, while higher PTEN levels typically turned up in tumors from the "differentiated" sub-group.

Overall, those involved argued that the study illustrates the value of bringing together expression and other genomic data with imaging information to better detect genetic signatures that may be obscured by stromal cell infiltration into tumors.