Increased angiogenesis is associated with a 32-gene expression signature and 6p21 amplification in aggressive endometrial cancer

// Ingunn M. Stefansson 1,2,* , Maria Raeder 1,3,* , Elisabeth Wik 1,2 , Monica Mannelqvist 1,2 , Kanthida Kusonmano 1,3 , Goril Knutsvik 1,2 , Ingfrid Haldorsen 4,5 , Jone Trovik 1,3 , Anne M. Oyan 1,6 , Karl-H. Kalland 1,6 , Anne Cathrine Staff 7 , Helga B. Salvesen 1,3 and Lars A. Akslen 1,2 1 Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway 2 Department of Pathology, Haukeland University Hospital, Bergen, Norway 3 Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway 4 Department of Radiology, Haukeland University Hospital, Postbox, Bergen, Norway 5 Section for Radiology, University of Bergen, Bergen, Norway 6 Department of Microbiology, Haukeland University Hospital, Bergen, Norway 7 Department of Obstetrics and Gynaecology, Women and Children’s Division, Oslo University Hospital, University of Oslo, Norway * These authors contributed equally to this work Correspondence to: Lars A. Akslen, email: // Keywords : angiogenesis, endometrial cancer, gene expression signature, prognosis Received : January 19, 2015 Accepted : February 17, 2015 Published : March 10, 2015 Abstract Background: Angiogenesis is a hallmark of cancer. The aim of this study was to explore whether microvessel proliferation is associated with gene expression profiles or copy number alterations in endometrial cancer. Methods: A prospective series of endometrial carcinomas was studied for angiogenesis markers, gene expression profiles, and gene copy number data. For validation, an independent series of endometrial carcinomas as well as an external cohort of endometrial cancer patients were examined by gene expression microarrays. Results: Increased microvessel proliferation (MVP) was associated with aggressive tumor features and reduced survival, and a 32-gene expression signature was found to separate tumors with high versus low MVP. An increased 32-gene signature score was confirmed to associate with high-grade tumor features and reduced survival by independent cohorts. Copy number studies revealed that amplification of the 6p21 region was significantly associated with MVP, a high 32-gene score, as well as reduced survival. Conclusion: Increased MVP was significantly associated with aggressive endometrial cancer and reduced survival. Integrated analyses demonstrated significant associations between increased vascular proliferation, amplification of the 6p21 region, VEGF-A mRNA expression, and the 32-gene angiogenesis signature. Our findings indicate amplification of 6p21 as a possible driver of tumor vascular proliferation in endometrial cancer.