Elsevier

Human Pathology

Volume 37, Issue 7, July 2006, Pages 781-786
Human Pathology

Perspective in pathology
B-RAF mutations in the etiopathogenesis, diagnosis, and prognosis of thyroid carcinomas

https://doi.org/10.1016/j.humpath.2006.03.013Get rights and content

Summary

The very recent discovery of B-RAF point mutations as the most prevalent genetic alteration in papillary thyroid carcinoma has revolutionized the molecular knowledge of thyroid malignancies. In this review, we address the role played by such mutations in the etiopathogenesis, diagnosis, prognosis, and therapy selection of thyroid cancer, with an emphasis on papillary carcinoma.

Introduction

Taking into consideration that 50% of the cases of human colon carcinoma present K-RAS mutations [1], Hanahan and Weinberg [2] speculated that the “remaining colonic tumors carry defects in other components of the growth signaling pathways that phenocopy RAS oncogene activation.”

In 2002, the Cancer Genome Project reported a high frequency in human malignancies of somatic activating mutations in a gene of the RAS-RAF-MEK-ERK pathway other than RASB-RAF [3]. Raf proteins are key members of the signaling pathway that are transducers of extracellular signals, through Ras small-GTPases, into the nucleus, in the signaling initiated by membrane receptor tyrosine kinases (RTK). Upon ligand binding (growth factors), RTKs are activated, therefore promoting the activation of guanine exchange factors such as Son of Sevenless. Activated guanine exchange factors promote the exchange of RAS-bound guanosine diphosphate by guanosine triphosphate, thus leading to a RAS active conformation. In fact, oncogenic RAS gene mutations stabilize RAS into a guanosine triphosphate–bound, hence constitutively active, form [4]. Active RAS, on its turn, recruits RAF to the membrane where it is activated (for a review, see Ref. [5]). Once activated, Raf proteins trigger the phosphorylation cascade of the “mitogen-activated protein kinase” pathway RAF-MEK-ERK. Of the several RAF isoforms, B-RAF appears to be the strongest activator of RAF-MEK-ERK pathway [6].

The study by Davies et al [3] and subsequent studies ascertained that B-RAF is mutated in a wide range of cancers, namely, in melanoma (63%-66%) [3], [7] and, in smaller frequencies, invasive micropapillary serous ovarian carcinoma (33%-40%) [3], [8] and colorectal carcinoma (11%-20%) [3], [9], [10]. In all these studies, B-RAF and RAS gene mutations were found to be mostly noncoexistent in the same tumor, being advanced; either way, each one would lead to the activation of the RAS-RAF-MEK-ERK pathway, thus confirming the hypothesis of Hanahan and Weinberg [2].

Almost all B-RAF mutations are clustered in 2 regions within the kinase domain: the glycine-rich loop that anchors adenosine triphosphate phosphates and is encoded by exon 11 and the activation loop, a phosphoregulatory region in which phosphorylations are required for full activity that is encoded by exon 15 [3]. The great majority of the mutations target the activation segment (>80%), and within it, a single mutation accounts for more than 90% of the cases [6]: a thymine for adenine transition at the nucleotide 1799 that leads to the substitution of a valine for a glutamic acid at the residue 600—B-RAFV600E (previously named as nucleotide 1796 and residue 599 [11]).

Section snippets

B-RAF mutations in thyroid tumors

RAS mutations have been known for a long time to occur frequently in lesions of the follicular cell lineage, namely, in follicular adenoma (FTA) (14%-33%) [12], [13], [14], [15], [16] and follicular carcinoma (FTC) (21%-50%) [13], [15], [16], and less frequently, in papillary thyroid carcinoma (PTC) (0%-21%) [12], [13], [15], [17].

Several screening studies performed in thyroid tumors consistently described high B-RAF mutation prevalences in PTC, ranging from 29% to 83% [18], [19], [20], [21],

B-RAF mutations in the etiopathogenesis of PTC

Known PTC genetic alterations other than B-RAF mutations are rearrangements of RET (RET/PTC) and NTRK1 genes and RAS gene point mutations. In some studies, these genetic events were screened together with B-RAF mutations, with prevalences of 8% to 33% for RET/PTC [18], [20], [43], [44], [45], 15% to 5% for NTRK1 rearrangements [44], [45], and 0% to 21% for RAS genes mutations [18], [20], [21], [44], [45]. These genetic events, B-RAF mutations included, are almost always noncoexistent in the

Genotype-phenotype associations in PTC

There seems to exist a trend toward an association between PTC histotypes and particular genetic alterations. The RET/PTC1 rearrangement is commonly associated with the conventional histotype [56], [57], [58], whereas RET/PTC3 rearrangement is correlated with the solid variant, particularly in the post-Chernobyl setting [59], [60], [61], [62], as well as with the tall cell variant [63]. By their turn, the activating mutations of RAS (mainly targeting codon 61 of N- and H-RAS) are particularly

Diagnostic value of B-RAF mutations

Given the specificity, within thyroid neoplasias, of B-RAF mutations to PTC, it is tempting to use their screening in the diagnosis of PTC. Molecular biology techniques were applied for the screening of B-RAF mutations, as well as of RET/PTC, in fine needle aspirates. The results obtained in these studies support the conclusion that the search for genetic alterations may be valuable in fine needle aspirates of thyroid lesions [65], [66], [69], [70], [71], [72]. Yet, the close relationship

Prognostic value of B-RAF mutations

Several clinicopathologic studies, as well as functional studies using thyroid-targeted B-RAFV600E transgenic mice [55] and B-RAFV600E-transfected thyroid cell lines [47], point to a higher aggressiveness of the B-RAF–mutated PTC cases. Some groups reported an association between B-RAF mutations and poor prognostic indicators, namely, the older age [23], [24], increased male incidence [21], extrathyroid extension [23], [75], regional metastases [25], [75], distant metastases [22], higher tumor

Therapeutic perspectives

The standard treatment of PTCs is well established and has provided excellent results in most cases. There are, nevertheless, several PTCs that carry a guarded prognosis and raise difficult therapeutic problems. It is conceivable that the information on B-RAF status may be important in the future to treat patients with primary, or most likely, recurrent PTCs responding badly to radioactive iodine. The same holds true for treating patients with B-RAF–mutated, poorly differentiated and

Acknowledgments

The authors thanks the colleagues of the Thyroid Group for their support and collaboration. Some of the work herein cited was supported by the Portuguese Science and Technology Foundation (FCT), both by a PhD grant to Vítor Trovisco (SFRH/BD/13055/2003) and by a project funding (POCTI project POCI/SAU-0BS/56175/2004).

We would like to apologize to the authors whose works were not cited because of space constraints or unintended omission.

References (77)

  • N. Thompson et al.

    Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery

    Curr Opin Pharmacol

    (2005)
  • H. Davies et al.

    Mutations of the BRAF gene in human cancer

    Nature

    (2002)
  • M.R. Ahmadian et al.

    Guanosine triphosphatase stimulation of oncogenic Ras mutants

    Proc Natl Acad Sci U S A

    (1999)
  • W. Kolch

    Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

    Biochem J

    (2000)
  • M.S. Brose et al.

    BRAF and RAS mutations in human lung cancer and melanoma

    Cancer Res

    (2002)
  • G. Singer et al.

    Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma

    J Natl Cancer Inst

    (2003)
  • H. Rajagopalan et al.

    Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status

    Nature

    (2002)
  • L. Wang et al.

    BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair

    Cancer Res

    (2003)
  • R. Kumar et al.

    Activating BRAF and N-Ras mutations in sporadic primary melanomas: an inverse association with allelic loss on chromosome 9

    Oncogene

    (2003)
  • H. Namba et al.

    Point mutations of ras oncogenes are an early event in thyroid tumorigenesis

    Mol Endocrinol

    (1990)
  • T. Oyama et al.

    N-ras mutation of thyroid tumor with special reference to the follicular type

    Pathol Int

    (1995)
  • C.T. Esapa et al.

    Prevalence of Ras mutations in thyroid neoplasia

    Clin Endocrinol (Oxf)

    (1999)
  • V. Vasko et al.

    Specific pattern of RAS oncogene mutations in follicular thyroid tumors

    J Clin Endocrinol Metab

    (2003)
  • P. Castro et al.

    PAX8-PPAR{gamma} rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma

    J Clin Endocrinol Metab

    (2006)
  • E.T. Kimura et al.

    High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma

    Cancer Res

    (2003)
  • Y. Cohen et al.

    BRAF mutation in papillary thyroid carcinoma

    J Natl Cancer Inst

    (2003)
  • P. Soares et al.

    BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC

    Oncogene

    (2003)
  • X. Xu et al.

    High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines

    Cancer Res

    (2003)
  • H. Namba et al.

    Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers

    J Clin Endocrinol Metab

    (2003)
  • M.N. Nikiforova et al.

    BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas

    J Clin Endocrinol Metab

    (2003)
  • V. Trovisco et al.

    Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients' age but not with tumour aggressiveness

    Virchows Arch

    (2005)
  • K.H. Kim et al.

    Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population

    Yonsei Med J

    (2004)
  • T. Fukushima et al.

    BRAF mutations in papillary carcinomas of the thyroid

    Oncogene

    (2003)
  • V. Trovisco et al.

    BRAF mutations are associated with some histological types of papillary thyroid carcinoma

    J Pathol

    (2004)
  • J. Lima et al.

    BRAF mutations are not a major event in post-chernobyl childhood thyroid carcinomas

    J Clin Endocrinol Metab

    (2004)
  • M. Xing et al.

    BRAF T1796A transversion mutation in various thyroid neoplasms

    J Clin Endocrinol Metab

    (2004)
  • A. Perren et al.

    BRAF and endocrine tumors: mutations are frequent in papillary thyroid carcinomas, rare in endocrine tumors of the gastrointestinal tract and not detected in other endocrine tumors

    Endocr Relat Cancer

    (2004)
  • P. Soares et al.

    BRAF mutations typical of papillary thyroid carcinoma are more frequently detected in undifferentiated than in insular and insular-like poorly differentiated carcinomas

    Virchows Arch

    (2004)
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