Influence of RET mutations on the expression of tyrosine kinases in medullary thyroid carcinoma

Rodríguez‐Antona, Cristina; Muñoz-Repeto, Iván; Inglada-Pérez, Lucía; Cubas, Aguirre A. de; Mančíková, Veronika; Cañamero, Marta; Maliszewska, Agnieszka; Gomez, A Herrera; Letón, Rocío; Leandro‐García, Luis Javier; Comino-Méndez, Iñaki; Sánchez, Lara Juan Emmanuel; Álvarez-Escolá, Cristina; Aller, Javier; Cascón, Alberto; Robledo, Mercedes

doi:10.1530/erc-12-0316

Cited by 18 publications

(11 citation statements)

References 29 publications

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“…Thus, Maliszewska et al (8) reported upregulation of genes involved in the Wnt, Notch, NF-κB, JAK/STAT and MAPK signalling pathways in sporadic MTC harbouring the Met918Thr RET mutation. A RET-associated expression of tyrosine kinases was also described by Rodriguez-Antona et al (9), whereby MTC with RET wildtype status showed a lower protein expression of PDGFRB than MTC with a somatic RET mutation.…”

Section: Introductionsupporting

confidence: 52%

Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients

Tiedje¹,

Ting

Walter

et al. 2016

European Journal of Endocrinology

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Objective: Medullary thyroid carcinoma (MTC) occurs sporadically in 75% of patients. Metastatic disease is associated with significantly poorer survival. The aim of this study was to identify prognostic markers for progressive MTC and oncogenic factors associated with response to vandetanib therapy. Design and methods: Clinical courses of 32 patients with sporadic MTC (n = 10 pN0cM0, n = 8 pN1cM0, n = 14 pN1cM1) were compared with genetic profiles of the patients' primary tumour tissue. Analysis for RET proto-oncogene mutations was performed by Sanger sequencing and next-generation sequencing (NGS). The mRNA expression (mRNA count) of 33 targets was measured by nCounter NanoString analysis. Results: Somatic RET mutations occurred in 21/32 patients. The RET918 mutation was found in 8/14 pN1cM1 patients. BRAF (P = 0.019), FGFR2 (P = 0.007), FGFR3 (P = 0.044) and VEGFC (P = 0.042) mRNA expression was significantly lower in pN1cM0/pN1cM1 compared with pN0cM0 patients, whereas PDGFRA (P = 0.026) mRNA expression was significantly higher in pN1cM0/pN1cM1 when compared with pN0cM0 patients. Among the 10/32 vandetanib-treated patients, 5 showed partial response (PR), all harbouring the RET918 mutation. mRNA expression of FLT1 (P = 0.039), FLT4 (P = 0.025) and VEGFB (P = 0.042) was significantly higher in therapy responders. Conclusions: In this study, we identified molecular markers in primary tumour tissue of sporadic MTC associated with the development of metastasis (both lymph node and organ metastasis) as well as response to vandetanib therapy.

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Section: Introductionsupporting

confidence: 52%

Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients

Tiedje¹,

Ting

Walter

et al. 2016

European Journal of Endocrinology

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“…Angiogenesis is a very complex process mediated by the coordinated activities of stimulatory and inhibitory factors. Published data on the expression of these factors in MTC are scarce, and most regard a limited set of proangiogenic proteins (generally, VEGF, PDGFRb and VEGFR1, 2 and 3) (Rodriguez-Antona et al 2013, Mancikova et al 2014. No attempt has been made to quantitatively assess angiogenesis activation in MTCs as a function of the tumor's mutation profile.…”

Section: Discussionmentioning

confidence: 99%

RET mutation and increased angiogenesis in medullary thyroid carcinomas

Verrienti¹,

Tallini²,

Colato³

et al. 2016

Endocrine-Related Cancer

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Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs. RET mutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors. We examined 45 MTCs with germ-line or somatic RET mutations (RETmut group) and 34 with wildtype RET (RETwt). Taqman Low-Density Arrays were used to assess proangiogenic gene expression. Immunohistochemistry was used to assess intratumoral, peritumoral and nontumoral expression levels of VEGFR1, R2, R3, PDGFRa, PDGFB and NOTCH3. We also assessed microvessel density (MVD) and lymphatic vessel density (LVD) based on CD31-positive and podoplanin-positive vessel counts, respectively, and vascular pericyte density based on staining for a-smooth muscle actin (a-SMA), a pericyte marker. Compared with RETwt tumors, RETmut tumors exhibited upregulated expression of proangiogenic genes (mRNA and protein), especially VEGFR1, PDGFB and NOTCH3. MVDs and LVDs were similar in the two groups. However, microvessels in RETmut tumors were more likely to be a-SMA positive, indicating enhanced coverage by pericytes, which play key roles in vessel sprouting, maturation and stabilization. These data suggest that angiogenesis in RETmut MTCs may be more intense and complete than that found in RETwt tumors, a feature that might increase their susceptibility to antiangiogenic therapy. Given their increased vascular pericyte density, RETmut MTCs might also benefit from combined or preliminary treatment with PDGF inhibitors. 23:8Research A Verrienti et al.Increased angiogenesis in RET-mutated MTCs RET mutation and increased angiogenesis in medullary thyroid carcinomas

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“…For Glut-1 a strong correlation (OR 4.2) was found, the lack of significance might be best explained by the relative low number of Glut-1 positive tumors (5.4%). Cytoplasmic staining of VEGF was seen in all MTCs however in a varying degree, we interpreted the VEGF staining as positive when there was a moderate to strong reactivity [20, 21]. No significant correlation was found with HIF-1α, however VEGF is known to be upregulated by RET mutations and sporadic RET mutations are not included in our data [20].…”

Section: Discussionmentioning

confidence: 99%

Expression of HIF-1α in medullary thyroid cancer identifies a subgroup with poor prognosis

et al. 2017

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BackgroundMedullary thyroid cancer (MTC) comprises only 4% of all thyroid cancers and originates from the parafollicular C-cells. HIF-1α expression has been implied as an indicator of worse prognosis in various solid tumors. However, whether expression of HIF-1α is a prognosticator in MTC remained unclear. Our aim was to evaluate the prognostic value of HIF-1α in patients with MTC.MethodsAll patients with MTC who were operated on between 1988 and 2014 in five tertiary referral centers in The Netherlands were included. A tissue microarray was constructed in which 111 primary tumors could be analyzed for expression of HIF-1α, CAIX, Glut-1, VEGF and CD31 and correlated with clinicopathologic variables and survival.ResultsThe mean age of patients was 46.3 years (SD 15.6), 59 (53.2%) were male. Of the 111 primary tumors, 49 (44.1%) were HIF-1α negative and 62 (55.9%) were HIF-1α positive. Positive HIF-1α expression was an independent negative indicator for progression free survival (PFS) in multivariate cox regression analysis (HR 3.1; 95% CI 1.3 – 7.3). Five-years survival decreased from 94.0% to 65.9% for the HIF-1α positive group (p=0.007). Even within the group of patients with TNM-stage IV disease, HIF-1α positivity was associated with a worse prognosis, shown by a decrease in 5-years survival of 88.0% to 49.3% (p=0.020).ConclusionExpression of HIF-1α is strongly correlated with adverse prognosis of MTC. This could open up new ways for targeted systemic therapy of MTC.

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Influence of RET mutations on the expression of tyrosine kinases in medullary thyroid carcinoma

Cited by 18 publications

References 29 publications

Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients

Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients

RET mutation and increased angiogenesis in medullary thyroid carcinomas

Expression of HIF-1α in medullary thyroid cancer identifies a subgroup with poor prognosis

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