The role of microRNA genes in papillary thyroid carcinoma

He, Hulling; Jażdżewski, Krystian; Li, Wei; Liyanarachchi, Sandya; Nagy, Rebecca; Volinia, Stefano; Calin, George A.; Liu, Chang Gong; Franssila, Kaarle; Suster, Saul; Kloos, Richard T.; Croce, Carlo M.; Chapelle, Albert de la

doi:10.1073/pnas.0509603102

Cited by 1,103 publications

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“…This mutation has been previously reported in one patient with papillary thyroid carcinoma. 34 We conclude from our data that in Merkel cell carcinoma, expression of KIT and occurrences of activating mutations in the receptor may be unrelated events. This is true in other tumors as well, such as solid psuedopapillary neoplasms of the pancreas, 35 melanomas, 36,37 pulmonary small cell carcinomas 38,39 and breast carcinomas.…”

Section: Discussionmentioning

confidence: 57%

“…In the absence of activating mutations in KIT, this paracrine stimulation may be the basis for tumor proliferation in Merkel cell carcinoma. Alternatively, downregulation of miRNAs, such as miRNA-221 and miRNA-222 which regulate KIT expression by binding to its 3 0 -UTR, 34,45,46 or an unknown mutation in the miRNA recognition site, can also result in receptor expression in the absence of gene amplification or mutations in KIT. This posttranscriptional regulation may also explain the absence of KIT expression in some of our cases of Merkel cell carcinoma, even in the presence of lesional SCF.…”

Section: Discussionmentioning

confidence: 99%

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Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Kartha

Sundram

2008

Modern Pathology

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Merkel cell carcinoma is a rare and aggressive form of skin cancer of neuroendocrine origin. Its treatment involves wide excision and radiotherapy but no effective therapy exists for advanced disease. Upregulation of the platelet-derived growth factor receptor family of tyrosine kinases, PDGFRA and KIT, has a crucial role in cancer development. Several studies have shown expression of the tyrosine kinase receptor KIT (CD117) in Merkel cell carcinoma. In this study, we examined the expression and mutational status of KIT and PDGFRA in 14 primary and 18 metastatic Merkel cell carcinoma. The expression of KIT and PDGFRA and their respective ligands, stem cell factor (SCF) and PDGFA, was assessed by immunohistochemistry. In addition, we analyzed KIT exons 9, 11, 13 and 17, and PDGFRA exons 10, 12 and 18 for the presence of activating mutations. We found that only 53% of cases of Merkel cell carcinoma expressed KIT, which was mostly seen as diffuse weak staining, and SCF expression was observed only in 31% of cases. In contrast, 87 and 81% of cases expressed PDGFRA and PDGFA, respectively. We observed coexpression of SCF and KIT in only 5 of 32 cases (16%) whereas 25 of 31 cases (81%) showed coexpression of PDGFRA and its ligand PDGFA. While we documented silent mutations in exon 17 of KIT and exons 10, 12 and 18 of PDGFRA, we were not able to identify any known activating mutations. Our results indicate that there is no correlation between positive immunostaining and occurrence of activating mutations in KIT and PDGFRA. Moreover, the presence of KIT/SCF and PDGFRA/PDGFA coexpression in a proportion of cases may indicate an autocrine/paracrine stimulation loop. We think therefore that imatinib mesylate is less likely to be an effective therapy for Merkel cell carcinoma, unless activating mutations exist in other exons of these receptor kinases.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Kartha

Sundram

2008

Modern Pathology

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“…In one of the first studies to illustrate this, He et al (2005a) observed that in 5 of 10 thyroid cancer cases analyzed where the upregulation of miR-221, -222 and -146 was highest, there was a corresponding loss of KIT transcript and Kit protein in addition to germ-line single nucleotide changes in the two recognition sequences in KIT for these miRNAs in its 3 0 UTR. Owing to the high familial incidence, these single nucleotide polymorphic changes are hypothesized to predispose this group of carriers to thyroid cancer.…”

Section: Introductionmentioning

confidence: 96%

“…These differences can classify different tumor types and tumor grades. Certain miRNA signatures are correlated with prognosis and can potentially be used to determine the specific course of treatment (Takamizawa et al, 2004;He et al, 2005a;Lu et al, 2005;Yanaihara et al, 2006;Shell et al, 2007;Visone et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Papillary thyroid carcinoma (PTC) is the most common malignancy in thyroid tissue. Profiling of PTC by He et al (2005a) yielded a signature of five miRNAs (which included miR-221, miR-222 and miR-146) that can separate PTC from normal thyroid. Bloomston et al (2007) showed that a signature of 21 upregulated and 4 downregulated miRNAs correctly differentiated pancreatic cancer from benign pancreatic tissue in 90% of samples.…”

Section: Introductionmentioning

confidence: 99%

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