Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis
- Cristina Rodríguez-Antona1,2,
- Judith Pallares3,
- Cristina Montero-Conde1,
- Lucia Inglada-Pérez1,2,
- Esmeralda Castelblanco3,6,
- Iñigo Landa1,
- Susanna Leskelä1,
- Luis J Leandro-García1,
- Elena López-Jiménez1,
- Rocío Letón1,
- Alberto Cascón1,2,
- Enrique Lerma4,
- M Carmen Martin5,
- M Carmen Carralero5,
- Didac Mauricio6,
- Juan Cruz Cigudosa2,5,
- Xavier Matias-Guiu3 and
- Mercedes Robledo1,2
- 1Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
2ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
3Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Lleida, Spain
4Pathology Service, Santa Creu and Sant Pau Hospital, Barcelona, Spain
5Molecular Cytogenetics Group, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO), Madrid, Spain
6Department of Endocrinology, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Lleida, Spain
- (Correspondence should be addressed to M Robledo at Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO); Email: mrobledo{at}cnio.es)
Abstract
Therapeutic options for patients with metastatic medullary thyroid carcinoma (MTC) are limited due to lack of effective treatments. Thus, there is a need to thoroughly characterize the pathways of molecular pathogenesis and to identify potential targets for therapy in MTC. Since epidermal growth factor receptor (EGFR) seems to play a crucial role for RET activation, a key feature of MTCs, and several promising EGFR/vascular endothelial growth factor receptor 2 (VEGFR2)-targeted drugs have been developed, the present study was designed to investigate whether these proteins are altered in MTCs. We used a well-characterized series of 153 MTCs to evaluate EGFR activation by sequencing and FISH analysis, and to perform EGFR and VEGFR2 immunohistochemistry. EGFR tyrosine kinase domain mutations were not a feature of MTCs; however, EGFR polysomy and a strong EGFR expression were detected in 15 and 13% of the tumors respectively. Interestingly, EGFR was significantly overexpressed in metastases compared with primary tumors (35 vs 9%, P=0.002). We also studied whether specific RET mutations were associated with EGFR status, and found a decrease in EGFR polysomies (P=0.006) and a tendency towards lower EGFR expression for the most aggressive RET mutations (918, 883). Concerning VEGFR2, metastasis showed a higher expression than primary tumors (P=2.8×10−8). In this first study investigating the relationship between EGFR, RET, and VEGFR2 in a large MTC series, we found an activation of EGFR and VEGFR2 in metastasis, using both independent and matched primary/metastasis samples. This suggests that some MTC patients may benefit from existing anti-EGFR/VEFGR2 therapies, although additional preclinical and clinical evidence is needed.
- © 2010 Society for Endocrinology