Evidence of a Low Prevalence of Ras Mutations in a Large Medullary Thyroid Cancer Series

Ciampi, Raffaele; mian, caterina; Fugazzola, Laura; Cosci, Barbara; Romei, Cristina; Barollo, Susi; Cirello, Valentina; Bottici, Valeria; Marconcini, Giulia; Pelizzo, Maria Rosa; Borrello, Maria Grazia; Basolo, Fulvio; Ugolini, Clara; Materazzi, Gabriele; Pinchera, Aldo; Elisei, Rossella

doi:10.1089/thy.2012-0207

Cited by 46 publications

(94 citation statements)

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“…RAS mutation was detected in 26.5% of all sporadic MTC tumours, but when only RET-negative samples were considered, the prevalence of RAS mutation was 68.7%. A higher proportion of H-RAS mutation that constituted 72% of all detected RAS mutations was observed, which is consistent with all reported results [15,16,32] and comparable with studies published by Moura et al and Boichard et al that reported RAS mutations present in 68% and 81% of RET-negative sporadic MTC samples, respectively [14,16]. The results of different analyses of RAS mutations in MTC are controversial with reference to their different frequency reported by different studies.…”

Section: Discussionsupporting

confidence: 90%

“…However, when we look at Italian results only, some differences may also be noticed. Ciampi et al reported a very low prevalence of RAS mutation in RET-negative sporadic MTC (17.6%) [32] while in the Scarpa and Fugazzola group the frequency of RAS mutation was 57% [31]. This percentage was even higher in our group -68.7 % of RET-negative tumours showed RAS mutation.…”

Section: Discussioncontrasting

confidence: 44%

“…The results of different analyses of RAS mutations in MTC are controversial with reference to their different frequency reported by different studies. Ciampi et al suggest that RAS mutations are extremely rare in MTC and stand for ~11% of all sporadic MTC cases and 17.6% when only RET-negative MTC samples were evaluated [33]. Schlumberger also reported such a low prevalence of RAS mutation in MTC, only in 8% of all sporadic MTC 34 .…”

Section: Discussionmentioning

confidence: 99%

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Częstość występowania mutacji somatycznych RAS w raku rdzeniastym tarczycy — analiza populacji polskiej

Oczko‐Wojciechowska

Pfeifer

Rusinek

et al. 2015

Endokrynologia Polska

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Introduction: Somatic RET mutations are detectable in two-thirds of sporadic cases of medullary thyroid cancer (MTC). Recent studies reported a high proportion of RAS somatic mutations in RET negative tumours, which may indicate RAS mutation as a possible alternative genetic event in sporadic MTC tumorigenesis. Thus, the aim of the study was to evaluate the frequency of somatic RAS mutations in sporadic medullary thyroid cancer in the Polish population and to relate the obtained data to the presence of somatic RET mutations. Material and methods: Somatic mutations (RET, RAS genes) were evaluated in 78 snap-frozen MTC samples (57 sporadic and 21 hereditary) by direct sequencing. Next, three randomly selected RET-negative MTC samples were analysed by the next generation sequencing. Results: RAS mutation was detected in 26.5% of 49 sporadic MTC tumours. None of all the analysed samples showed N-RAS mutation. When only RET-negative samples were considered, the prevalence of RAS mutation was 68.7%, compared to 6% observed in RET-positive samples. Most of these mutations were located in H-RAS codon 61 (72%). None of 21 hereditary MTC samples showed any RAS mutations.

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Section: Discussionsupporting

confidence: 90%

Section: Discussioncontrasting

confidence: 44%

Section: Discussionmentioning

confidence: 99%

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Częstość występowania mutacji somatycznych RAS w raku rdzeniastym tarczycy — analiza populacji polskiej

Oczko‐Wojciechowska

Pfeifer

Rusinek

et al. 2015

Endokrynologia Polska

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“…RET mutations are less common in sporadic MTCs, roughly half of which harbor somatic alterations of this gene (Wu et al 2011). In the last few years, somatic mutations in the RAS oncogenes have also been identified in sporadic MTCs, with reported prevalence rates ranging from 11% (Ciampi et al 2013) to 44% (Boichard et al 2015). Nevertheless, in a small proportion of sporadic MTCs, no genetic alterations are detected.…”

Section: Introductionmentioning

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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“…RET activation induces MET upregulation in thyrocytes (30,47) and thereby promotes motility and invasion (30). Mutational activation of RAS, which occurs in some MTC patients lacking RET mutations (48,49), also leads to MET upregulation (47).…”

Section: Cabozantinib Inhibits Tt Tumor Growthmentioning

confidence: 99%

In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer

Bentzien

Zuzow

Heald

et al. 2013

Thyroid

114

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Background: A limited number of approved therapeutic options are available to metastatic medullary thyroid cancer (MTC) patients, and the response to conventional chemotherapy and/or radiotherapy strategies is inadequate. Sporadic and inherited mutations in the tyrosine kinase RET result in oncogenic activation that is associated with the pathogenesis of MTC. Cabozantinib is a potent inhibitor of MET, RET, and vascular endothelial factor receptor 2 (VEGFR2), as well as other tyrosine kinases that have been implicated in tumor development and progression. The object of this study was to determine the in vitro biochemical and cellular inhibitory profile of cabozantinib against RET, and in vivo antitumor efficacy using a xenograft model of MTC. Methods: Cabozantinib was evaluated in biochemical and cell-based assays that determined the potency of the compound against wild type and activating mutant forms of RET. Additionally, the pharmacodynamic modulation of RET and MET and in vivo antitumor activity of cabozantinib was examined in a MTC tumor model following subchronic oral administration. Results: In biochemical assays, cabozantinib inhibited multiple forms of oncogenic RET kinase activity, including M918T and Y791F mutants. Additionally, it inhibited proliferation of TT tumor cells that harbor a C634W activating mutation of RET that is most often associated with MEN2A and familial MTC. In these same cells grown as xenograft tumors in nude mice, oral administration of cabozantinib resulted in dose-dependent tumor growth inhibition that correlated with a reduction in circulating plasma calcitonin levels. Moreover, immunohistochemical analyses of tumors revealed that cabozantinib reduced levels of phosphorylated MET and RET, and decreased tumor cellularity, proliferation, and vascularization. Conclusions: Cabozantinib is a potent inhibitor of RET and prevalent mutationally activated forms of RET known to be associated with MTC, and effectively inhibits the growth of a MTC tumor cell model in vitro and in vivo.

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Evidence of a Low Prevalence of Ras Mutations in a Large Medullary Thyroid Cancer Series

Cited by 46 publications

References 1 publication

Częstość występowania mutacji somatycznych RAS w raku rdzeniastym tarczycy — analiza populacji polskiej

Częstość występowania mutacji somatycznych RAS w raku rdzeniastym tarczycy — analiza populacji polskiej

RET mutation and increased angiogenesis in medullary thyroid carcinomas

In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer

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