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Clinical implications of BRAF mutation in thyroid carcinoma

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Significant progress has recently been made in the clinical management of papillary thyroid carcinoma. The accuracy of diagnosis and prognostic stratification of this type of carcinoma are high but still fall below 100%. Lack of effective treatments for advanced stage papillary thyroid carcinoma leads to death in some patients. Approximately half of all such carcinomas harbor mutations in the gene encoding the serine/threonine-kinase B-type Raf kinase (BRAF), resulting in constitutive activation of the mitogen-activated protein kinase–extracellular-signal-regulated kinases signal transduction pathway. There is intriguing evidence that BRAF mutation testing of papillary thyroid carcinoma might improve the diagnosis, prognostic stratification and treatment of these tumors but large, prospective trials are needed to define the actual clinical impact of these approaches.

Section snippets

BRAF mutation as a potential new clinical tool for thyroid cancer

Thyroid cancer, the most common endocrine malignancy, represents ∼1% of all malignancies in Western countries [1]. It is the cancer with the most rapidly increasing incidence rates in women and the second most rapid in men. With an annual percentage change of ∼5%, it is now the sixth most common cancer in women [2].

Over 80% of malignant thyroid tumors are papillary carcinomas [1]. Significant progress has been made in the clinical management of papillary thyroid cancer (PTC) [3] but there is

The molecular epidemiology of BRAF mutations in PTC

Raf (see Glossary) is a serine/threonine-selective protein kinase involved in the mitogen-activated protein kinase (MAPK) pathway [6] (Figure 1), whose constitutive activation leads to tumorigenesis. Of the three functional Raf isoforms described in humans, the most potent MAPK pathway activator is BRAF, which is encoded by a gene on chromosome 7 and is expressed in all cell types [6]. Large-scale genomic screens have detected BRAF mutations in 66% of all malignant melanomas and in some

Diagnostic relevance of BRAF mutations in thyroid lesion work-up

Fine-needle aspiration cytology (FNAC) is the most sensitive and specific method for identifying malignant thyroid nodules. In specialized centers, its diagnostic accuracy approaches 98%, with false-positive and false-negative rates of <2% [25]. However, 15% of thyroid nodule FNAs prove to be inadequate for cytological diagnosis, and in another 10% (generally involving follicular or Hürthle cell tumors), it is not possible to determine with certainty whether the nodule is an adenoma or

Prognostic significance of BRAF mutations

Prognostic characterization of PTCs is important for decisions regarding the initial treatment (e.g. surgery, with or without radioiodine ablation) and the aggressiveness of follow-up. The individual risk for tumor recurrence is conventionally evaluated based on age at diagnosis, tumor histology, tumor extension and the completeness of the surgical resection. One evident drawback of this routine is that it precludes full risk assessment at the preoperative phase. In addition, predictions based

BRAF as a therapeutic target in PTC

Targeted therapies for cancer tend to be most effective when the therapeutic compound inhibits a pathway that is constitutively activated during the early stages of tumor development, as is the case for the Raf–MAPK kinase (MEK)–ERK cascade in PTC 14, 53. Because the BRAF mutation predicts tumor sensitivity to MEK inhibition [54], selective inhibitors of BRAF kinase or its direct downstream effectors are logical candidates for the treatment of advanced PTCs [55]. Preclinical data support the

Conclusions and perspectives

Currently available data suggest potential roles for BRAF mutation testing in the management of PTC, although its field of application awaits further definition. BRAF mutation analysis of FNA specimens could theoretically help to distinguish between benign and malignant tumors when cytology is inconclusive. Unfortunately, inconclusive cytology generally arises with follicular neoplasms, which are not associated with BRAF mutations, or follicular PTC variants, in which BRAF mutations are rare.

Acknowledgements

This work was supported by grants from the Italian Ministry of Universities and Research (COFIN), the Italian Ministry of Health (Grant Ricerca Finalizzata – 2004) and the Italian Association for Cancer Research (AIRC) (to S. F.). Support was also received from the ‘Fondazione Umberto Di Mario ONLUS’ (to S.F.), from the “Banca d’Italia” (to S.F.) and from the ‘Fondazione Cassa di Risparmio di Perugia’ (to E.P.). C.D. is a PhD Fellow in the ’Endocrinology and Molecular Medicine’ Program at the

Glossary

Allele-specific LightCycler PCR
allele-specific LightCycler PCR is a mutation screening technique used to detect nucleotide point mutations. It is based on the ability of Real-Time LightCycler® Instruments to monitor the melting points of probes based on decreases in fluorescence. Higher melting points are indicative of more stable hybridization (binding) between the probe and its target. Mutations [e.g., single nucleotide polymorphisms (SNPs)] weaken probe binding and can easily be recognized.

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