Retinopathy Gene Signature Predicts Breast Cancer Survival

Photo Madical Retina Abnormal isolated on black background.Retina of diabetes   diabates retinopathy.

The pathology of retinopathy and cancer both derive from angiogenesis; the formation of new blood vessels from pre-existing ones. Not surprisingly, many treatments for both conditions are anti-angiogenesis therapies, especially those directed against vascular endothelial growth factors (VEGF). By studying the molecular angiogenic mechanisms in both conditions, researchers have identified a particular retinopathy gene signature with a strong prognostic association with breast cancer survival in some patients.

“Our results may lead to a better understanding of molecular mechanisms of pathological angiogenesis and its contribution to breast cancer,” the authors write in their paper on the findings appearing in PLOS Genetics.

The study was envisioned as a means to discover the genes and pathways associated with pathological angiogenesis, such as in retinopathy and cancer.

While VEGF therapies are frequently successful in treatment of retinopathy and some cancers, many patients either do not respond to anti-VEGF therapy, have incompletes responses, or become refractory to treatment. This study is an effort to develop a method for predicting patient response to anti-angiogenesis therapy. By understanding the mechanisms, the researchers hope to gain insight into developing new treatments for angiogenesis-dependent diseases.

“We propose that mRNA abundance gene signatures may have an important role in separating patients that would benefit from anti-VEGF therapy from those that do not,” the study authors write.

Mouse retinopathy model reveals 153 genes

To identify a gene cluster associated with angiogenesis, they first looked to a mouse model used extensively to study pathological angiogenesis in disease: the mouse retina in the oxygen-induced retinopathy (OIR) model.

In this study, researchers studied the OIR transcriptome of the mouse retina via RNA-seq. They discovered 153 genes were altered in OIR retinas compared with normal mouse retina. These genes were also found to be similar to a molecular signature relevant to other angiogenesis-dependent processes, like cancer.  Of the 153 mouse genes, the researchers identified 149 human equivalent genes.

“These results suggest that the OIR model reveals key genes involved in pathological angiogenesis,” the author write.” And these may find important applications in stratifying tumors for treatment intensification or for angiogenesis-targeted therapies.”

Correlation with breast cancer patients

Next, these genes were validated by building an angiogenesis signature with prognostic value for human breast cancer. They used a machine learning approach applied to the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset, a collection of 2,000 patient tumor samples, including mRNA abundance profiles and long-term clinical outcomes information, to evaluate the disease relevance of their angiogenic signature in these patients.

In their final analysis, they determined a final gene signature correlated with both OIR and breast cancer that involved 11 different genes.

They next sought to use the gene signature to classify breast cancer patients according to their predicted time of survival. An analysis of nearly 1,000 METABRIC patients found the model was able to separate patients into three groups with significantly different outcomes; low-risk (more than 15 years), intermediate-risk (between 7.5 and 15 years), and high-risk (less than 7.5 years).  Their model was linked to a 40 percent difference in the 15-year survival between the low-risk and high-risk patients.

Further, they saw that the signature was useful for breast cancers that respond to anti-VEGF therapy (basal, luminal A and B subtypes) but has no value to HER2+ breast cancer, which lacks a response to anti-VEGF therapy.

“Our results emphasize the contribution of hypoxia and VEGF-driven angiogenesis in specific subtypes of breast cancer,” the authors conclude. “It may also provide a new blueprint for the development of gene signatures and discovery of biomarkers for human disease.”

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