Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis.
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 x 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.
Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Cristina
C
Rodríguez-Antona
Judith
J
Pallares
Cristina
C
Montero-Conde
Lucia
L
Inglada-Pérez
Esmeralda
E
Castelblanco
Iñigo
I
Landa
Susanna
S
Leskelä
Luis J
LJ
Leandro-García
Elena
E
López-Jiménez
Rocío
R
Letón
Alberto
A
Cascón
Enrique
E
Lerma
M Carmen
MC
Martin
M Carmen
MC
Carralero
Didac
D
Mauricio
Juan Cruz
JC
Cigudosa
Xavier
X
Matias-Guiu
Mercedes
M
Robledo
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D018276:Carcinoma, Medullary / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000502:physiology; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D018773:Genes, erbB-1; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D055815:Young Adult
D009363:Neoplasm Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2