Somatic<i>RAS</i>Mutations Occur in a Large Proportion of Sporadic<i>RET</i>-Negative Medullary Thyroid Carcinomas and Extend to a Previously Unidentified Exon

Boichard, Amélie; Croux, L; Ghuzlan, A. Al; Broutin, Sophie; Dupuy, Corinne; Leboulleux, Sophie; Schlumberger, Martin; Bidart, Jean Michel; Lacroix, Ludovic

doi:10.1210/jc.2012-2092

Cited by 134 publications

(108 citation statements)

References 17 publications

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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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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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show abstract

“…Sporadic medullary thyroid carcinomas with wild-type RET genes may harbor RAS mutations (HRAS or KRAS). 2,4,5,8,15,16 D. PIK3CA, AKT1, and TP53 Mutational Analysis PIK3CA, AKT1, and TP53 mutations are usually found in advanced thyroid cancer with propensity for dedifferentiation and distant metastasis. 8,17 E. CTNNB1 Mutational Analysis…”

Section: Ras Mutational Analysismentioning

confidence: 99%

Template for Reporting Results of Biomarker Testing of Specimens From Patients With Thyroid Carcinoma

Chiosea

Sylvia

Berman

et al. 2016

Archives of Pathology &Amp; Laboratory Medicine

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“…The remaining MTC is derived from an autosomal dominant hereditary pattern associated with the RET proto-oncogene. Hereditary MTC is more likely to be multifocal and bilateral in nature [53][54][55][56][57][58][59]. Thirty percent of MTC affects patients younger than 50 and can have a familial inheritance pattern including the association with multiple endocrine neoplasia (MEN) syndromes.…”

Section: Medullary Thyroid Cancermentioning

confidence: 99%