Molecular diagnostics and predictors in thyroid cancer.

BACKGROUND The accuracy of cancer detection in thyroid nodules by fine-needle aspiration (FNA) cytology and prognostication of thyroid cancer needs further improvement and can benefit from testing for molecular alterations known to occur in thyroid tumors. SUMMARY Recent studies have demonstrated the feasibility of mutation detection in clinical FNA samples from thyroid nodules and their contribution to improving the diagnostic accuracy of FNA cytology. It appears that molecular testing is most beneficial for thyroid FNA samples with indeterminate cytology, where it can resolve the diagnosis in a significant number of cases. In addition to BRAF mutation, which has been studied most extensively, detection of RAS, RET/PTC, and PAX8/PPARgamma mutations also contribute substantially to cancer diagnosis. Some of these molecular markers, particularly BRAF, can also be used for tumor prognostication. In clinical setting, molecular testing of thyroid FNA samples and surgically removed tumors should utilize a restricted number of techniques that provide high accuracy and specificity of mutation detection. CONCLUSION Testing for cancer-specific mutations in thyroid FNA samples and surgically removed tumor tissues increases diagnostic accuracy of FNA cytology and offers better prognostication of thyroid cancer.

[1]  M. Santoro,et al.  Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma. , 1994, Oncogene.

[2]  Y. Nikiforov,et al.  Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. , 1997, Cancer research.

[3]  S. Filetti,et al.  BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. , 2007, The Journal of clinical endocrinology and metabolism.

[4]  L. Rowe,et al.  Utility of BRAF V600E mutation detection in cytologically indeterminate thyroid nodules , 2006, CytoJournal.

[5]  M. Nikiforova,et al.  PAX8-PPAR&ggr; Rearrangement in Thyroid Tumors: RT-PCR and Immunohistochemical Analyses , 2002, The American journal of surgical pathology.

[6]  D. Barford,et al.  Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF , 2004, Cell.

[7]  B. Cho,et al.  Detection of BRAFV600E mutation on fine needle aspiration specimens of thyroid nodule refines cyto‐pathology diagnosis, especially in BRAFV600E mutation‐prevalent area , 2006, Clinical endocrinology.

[8]  M. Santoro,et al.  PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas , 1990, Cell.

[9]  Stephanie L. Lee,et al.  Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. , 2009, Thyroid : official journal of the American Thyroid Association.

[10]  M. Nikiforova,et al.  Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. , 2009, The Journal of clinical endocrinology and metabolism.

[11]  A. El‐Naggar,et al.  Genetic Alterations and Their Relationship in the Phosphatidylinositol 3-Kinase/Akt Pathway in Thyroid Cancer , 2007, Clinical Cancer Research.

[12]  X. Qian,et al.  BRAF Mutation Analysis in Fine Needle Aspiration (FNA) Cytology of the Thyroid , 2006, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[13]  Gerard M Doherty,et al.  Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. , 2006, Thyroid : official journal of the American Thyroid Association.

[14]  Yuri E Nikiforov,et al.  RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. , 2003, The Journal of clinical endocrinology and metabolism.

[15]  R. Domingues,et al.  Searching for RET/PTC rearrangements and BRAF V599E mutation in thyroid aspirates might contribute to establish a preoperative diagnosis of papillary thyroid carcinoma , 2005, Cytopathology : official journal of the British Society for Clinical Cytology.

[16]  H. Namba,et al.  Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. , 2003, The Journal of clinical endocrinology and metabolism.

[17]  T. Giordano,et al.  HOOK3-RET: a novel type of RET/PTC rearrangement in papillary thyroid carcinoma. , 2007, Endocrine-related cancer.

[18]  C. Eng,et al.  A limited set of human MicroRNA is deregulated in follicular thyroid carcinoma. , 2006, The Journal of clinical endocrinology and metabolism.

[19]  M. Nikiforova,et al.  MicroRNA Expression Profiles in Thyroid Tumors , 2009, Endocrine pathology.

[20]  G. Tseng,et al.  MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. , 2008, The Journal of clinical endocrinology and metabolism.

[21]  A. Sacchi,et al.  PCR Amplification and Analysis of RAS Oncogenes from Thyroid Cytologic Smears , 1994, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[22]  D. Powell,et al.  The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. , 1998, Cancer research.

[23]  S. Asa,et al.  Prevalence of activating ras mutations in morphologically characterized thyroid nodules. , 1996, Thyroid : official journal of the American Thyroid Association.

[24]  C. Croce,et al.  The role of microRNA genes in papillary thyroid carcinoma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Gao,et al.  Analysis of Differential BRAFV600E Mutational Status in High Aggressive Papillary Thyroid Microcarcinoma , 2009, Annals of Surgical Oncology.

[26]  D. Ward,et al.  Frequent chromosomal DNA unbalance in thyroid oncocytic (Hürthle cell) neoplasms detected by comparative genomic hybridization. , 1999, Laboratory investigation; a journal of technical methods and pathology.

[27]  Tae Yong Kim,et al.  The BRAF mutation is useful for prediction of clinical recurrence in low‐risk patients with conventional papillary thyroid carcinoma , 2006, Clinical endocrinology.

[28]  V. Trovisco,et al.  PAX8-PPARγ rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma , 2006 .

[29]  Jeffrey E. Lee,et al.  Fine-needle aspiration of the thyroid and correlation with histopathology in a contemporary series of 240 patients. , 2003, American journal of surgery.

[30]  R. Camp,et al.  ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  H. Rabes,et al.  Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[32]  S. Asa,et al.  Pathogenetic mechanisms in thyroid follicular-cell neoplasia , 2006, Nature Reviews Cancer.

[33]  Electron Kebebew,et al.  The Prevalence and Prognostic Value of BRAF Mutation in Thyroid Cancer , 2007, Annals of surgery.

[34]  S. Groshen,et al.  Follicular lesions of thyroid , 2000, Cancer.

[35]  A. Sakamoto,et al.  Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. , 2000, Pathology, research and practice.

[36]  M. Xing,et al.  BRAF mutation in thyroid cancer. , 2005, Endocrine-related cancer.

[37]  M. Nikiforova,et al.  BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. , 2003, The Journal of clinical endocrinology and metabolism.

[38]  P. Ladenson,et al.  BRAF mutation in papillary thyroid carcinoma. , 2003, Journal of the National Cancer Institute.

[39]  R. Hofstra,et al.  RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. , 2006, Endocrine reviews.

[40]  D. Clark,et al.  Mutational Analysis of BRAF in Fine Needle Aspiration Biopsies of the Thyroid: A Potential Application for the Preoperative Assessment of Thyroid Nodules , 2004, Clinical Cancer Research.

[41]  P. Ladenson,et al.  BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. , 2005, The Journal of clinical endocrinology and metabolism.

[42]  L. Mariani,et al.  RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[43]  Yuri E Nikiforov,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. , 2003, Cancer research.

[44]  B. Caillou,et al.  Presence of mutations in all three ras genes in human thyroid tumors. , 1990, Oncogene.

[45]  A. Russo,et al.  BRAFV600E mutation and p27kip1 expression in papillary carcinomas of the thyroid ≤1 cm and their paired lymph node metastases , 2007 .

[46]  Masahiro Ito,et al.  A Rapid and Simple Detection Method for the BRAFT1796A Mutation in Fine-Needle Aspirated Thyroid Carcinoma Cells , 2004 .

[47]  P. Ladenson,et al.  BRAF mutation testing of thyroid fine-needle aspiration biopsy specimens for preoperative risk stratification in papillary thyroid cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  G. Chiappetta,et al.  Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. , 1996, Oncogene.

[49]  P. Ladenson,et al.  Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new diagnostic tool for papillary thyroid cancer. , 2004, The Journal of clinical endocrinology and metabolism.

[50]  M. Gariboldi,et al.  Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer , 2004, Oncogene.

[51]  Leslie R Rowe,et al.  Detection of BRAF V600E activating mutation in papillary thyroid carcinoma using PCR with allele-specific fluorescent probe melting curve analysis , 2007, Journal of Clinical Pathology.

[52]  V. Trovisco,et al.  BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC , 2003, Oncogene.

[53]  G. Troncone,et al.  Combined analysis of galectin-3 and BRAFV600E improves the accuracy of fine-needle aspiration biopsy with cytological findings suspicious for papillary thyroid carcinoma. , 2007, Endocrine-related cancer.

[54]  M. Nikiforova,et al.  Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity. , 2006, The Journal of clinical endocrinology and metabolism.

[55]  Lei Zhang,et al.  Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. , 2005, Cancer research.

[56]  E. Mazzaferri,et al.  Management of a solitary thyroid nodule. , 1993, The New England journal of medicine.

[57]  H. Gharib.  Changing trends in thyroid practice: understanding nodular thyroid disease. , 2004, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[58]  Stephen R. Master,et al.  Differential Expression of miRNAs in Papillary Thyroid Carcinoma Compared to Multinodular Goiter Using Formalin Fixed Paraffin Embedded Tissues , 2007, Endocrine pathology.

[59]  M. Borrello,et al.  Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas. , 1994, Cancer research.

[60]  N. Lemoine,et al.  High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. , 1989, Oncogene.

[61]  A. Pinchera,et al.  BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. , 2008, The Journal of clinical endocrinology and metabolism.

[62]  Jean Gaudart,et al.  Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma. , 2004, European journal of endocrinology.

[63]  G. Fontanini,et al.  N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression. , 2000, Thyroid : official journal of the American Thyroid Association.

[64]  E. Kaplan,et al.  N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma. , 1994, Surgery.

[65]  G. Chiappetta,et al.  RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[66]  A. Pinchera,et al.  A morpho-molecular diagnosis of papillary thyroid carcinoma: BRAF V600E detection as an important tool in preoperative evaluation of fine-needle aspirates. , 2009, Thyroid : official journal of the American Thyroid Association.

[67]  H. Namba,et al.  Clinical implications of pre-operative rapid BRAF analysis for papillary thyroid cancer. , 2007, Endocrine journal.

[68]  E. Kaplan,et al.  N-ras 61 oncogene mutations in Hürthle cell tumors. , 1990, Surgery.

[69]  C. Esapa,et al.  Prevalence of Ras mutations in thyroid neoplasia , 1999, Clinical endocrinology.

[70]  M. Santoro,et al.  Mutation of the PIK3CA gene in anaplastic thyroid cancer. , 2005, Cancer research.

[71]  C. Croce,et al.  MicroRNA deregulation in human thyroid papillary carcinomas. , 2006, Endocrine-related cancer.

[72]  S. Rubin,et al.  Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. , 1990, Molecular endocrinology.

[73]  T. Dwight,et al.  Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. , 2003, The Journal of clinical endocrinology and metabolism.

[74]  C. Croce,et al.  MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle. , 2007, Endocrine-related cancer.

[75]  Simion I. Chiosea,et al.  A Novel Complex BRAF Mutation Detected in a Solid Variant of Papillary Thyroid Carcinoma , 2009, Endocrine pathology.

[76]  Y. Nikiforov.  RET/PTC rearrangement in thyroid tumors , 2002, Endocrine pathology.

[77]  M. Latteri,et al.  Fine-needle aspiration molecular analysis for the diagnosis of papillary thyroid carcinoma through BRAF V600E mutation and RET/PTC rearrangement. , 2007, Thyroid : official journal of the American Thyroid Association.

[78]  Y. Nikiforov,et al.  Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. , 2004, The Journal of clinical endocrinology and metabolism.

[79]  Z. Baloch,et al.  Diagnosis of “follicular neoplasm”: A gray zone in thyroid fine‐needle aspiration cytology , 2002, Diagnostic cytopathology.

[80]  Y. Jo,et al.  Diagnostic value of pyrosequencing for the BRAFV600E mutation in ultrasound‐guided fine‐needle aspiration biopsy samples of thyroid incidentalomas , 2009, Clinical endocrinology.

[81]  W. Kim,et al.  Pyrosequencing Analysis for Detection of a BRAFV600E Mutation in an FNAB Specimen of Thyroid Nodules , 2008, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[82]  G. Troncone,et al.  Detection of RET/PTC, TRK and BRAF mutations in preoperative diagnosis of thyroid nodules with indeterminate cytological findings , 2007, Clinical endocrinology.

[83]  F. Wyllie,et al.  Activated ras oncogenes in human thyroid cancers. , 1988, Cancer research.

[84]  P. Kastner,et al.  Heterogeneity in the distribution of RET/PTC rearrangements within individual post-Chernobyl papillary thyroid carcinomas. , 2004, The Journal of clinical endocrinology and metabolism.

[85]  T. Fahey,et al.  MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma , 2008, Modern Pathology.

[86]  J. Garber,et al.  Genetic and biological subgroups of low-stage follicular thyroid cancer. , 2003, The American journal of pathology.

[87]  A. Thor,et al.  Ras oncogene mutations in benign and malignant thyroid neoplasms. , 1991, The Journal of clinical endocrinology and metabolism.

[88]  E. Mazzaferri.  Management of low-risk differentiated thyroid cancer. , 2007, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[89]  M. Pierotti,et al.  Selective activation of ras oncogenes in follicular and undifferentiated thyroid carcinomas. , 1994, European journal of cancer.

[90]  G. Fuller,et al.  RET Oncogene Activation in Papillary Thyroid Carcinoma , 2001, Advances in anatomic pathology.

[91]  M. A. García-Cabezas,et al.  The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane. , 2006, Endocrine-related cancer.

[92]  Juan Rosai,et al.  Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: A synopsis of the National Cancer Institute Thyroid Fine‐Needle Aspiration State of the Science Conference , 2008, Diagnostic cytopathology.

[93]  D. Sidransky,et al.  BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment , 2004, Modern Pathology.

[94]  E. Roti,et al.  BRAF V600E mutation analysis increases diagnostic accuracy for papillary thyroid carcinoma in fine-needle aspiration biopsies. , 2009, European journal of endocrinology.

[95]  M. Santoro,et al.  Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. , 2007, The Journal of clinical endocrinology and metabolism.

[96]  I D Hay,et al.  Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. , 1992, The Journal of clinical investigation.

[97]  N. Katabi,et al.  Follicular variant of papillary thyroid carcinoma , 2006, Cancer.

[98]  T. Giordano,et al.  Correlation Between Genetic Alterations and Microscopic Features, Clinical Manifestations, and Prognostic Characteristics of Thyroid Papillary Carcinomas , 2006, The American journal of surgical pathology.

[99]  M. Ladanyi,et al.  Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. , 2009, Cancer research.

[100]  G. Troncone,et al.  Detection of BRAF mutation in thyroid papillary carcinomas by mutant allele-specific PCR amplification (MASA). , 2006, European journal of endocrinology.

[101]  M. Xing,et al.  BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. , 2007, Endocrine reviews.