RAS Mutations in Thyroid Cancer

In recent years, our understanding of the genetic alterations underlying thyroid oncogenesis has greatly expanded. Theuseofmolecularmarkers, includingRAS, in the management of thyroid carcinoma is also increasing. This review summarizes the current literature surrounding RAS anddiscusses its potential as a diagnostic andprognostic indicator in themanagement of thyroid cancer. TheOncologist 2013;18:926–932 Implications for Practice: In recent years, our understanding of themolecular mechanisms underlying thyroid oncogenesis has greatly expanded. Further, the use of somemolecularmarkers in the clinical management of thyroid cancer is increasing.Mutations in RAS represent the second most common genetic event in thyroid neoplasia. However, the significance of RAS-positive mutation status and thebiological behavior of thyroid carcinomas that harborRAS arenot completely understood. Thepurposes of this revieware to clarify the current literature surroundingRASmutations in thyroid cancer and toexamine thepotential utility ofRAS as a diagnostic tool to predict the presence ofmalignancy, thus altering subsequent clinicalmanagement. In addition, the prognostic value of RAS positivity in predicting the risk for tumor aggressiveness, recurrence, andmortality is discussed.

[1]  R. Seethala,et al.  RAS mutations in thyroid FNA specimens are highly predictive of predominantly low-risk follicular-pattern cancers. , 2013, The Journal of clinical endocrinology and metabolism.

[2]  M. Borrello,et al.  Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series. , 2012, Thyroid : official journal of the American Thyroid Association.

[3]  S. Broutin,et al.  Somatic RAS mutations occur in a large proportion of sporadic RET-negative medullary thyroid carcinomas and extend to a previously unidentified exon. , 2012, The Journal of clinical endocrinology and metabolism.

[4]  Y. Miyagi,et al.  The associations between RAS mutations and clinical characteristics in follicular thyroid tumors: new insights from a single center and a large patient cohort. , 2012, Thyroid : official journal of the American Thyroid Association.

[5]  A. Hoff,et al.  Recent advances in the molecular pathogenesis and targeted therapies of medullary thyroid carcinoma , 2012, Current opinion in oncology.

[6]  R. Seethala,et al.  Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples. , 2011, The Journal of clinical endocrinology and metabolism.

[7]  V. Leite,et al.  High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. , 2011, The Journal of clinical endocrinology and metabolism.

[8]  W. Salameh,et al.  Well differentiated follicular thyroid neoplasia: Impact of molecular and technological advances on detection, monitoring and treatment , 2011, Molecular and Cellular Endocrinology.

[9]  B. Ljung,et al.  Molecular Testing for Somatic Mutations Improves the Accuracy of Thyroid Fine-needle Aspiration Biopsy , 2010, World Journal of Surgery.

[10]  M. Xing,et al.  Genetic alterations in the phosphatidylinositol-3 kinase/Akt pathway in thyroid cancer. , 2010, Thyroid : official journal of the American Thyroid Association.

[11]  F. Pacini,et al.  Impact of proto-oncogene mutation detection in cytological specimens from thyroid nodules improves the diagnostic accuracy of cytology. , 2010, The Journal of clinical endocrinology and metabolism.

[12]  R. Seethala,et al.  Contribution of molecular testing to thyroid fine‐needle aspiration cytology of “follicular lesion of undetermined significance/atypia of undetermined significance” , 2010, Cancer cytopathology.

[13]  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.

[14]  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.

[15]  Yuri E Nikiforov,et al.  Thyroid carcinoma: molecular pathways and therapeutic targets , 2008, Modern Pathology.

[16]  B. Ljung,et al.  The National Cancer Institute Thyroid fine needle aspiration state of the science conference: a summation , 2008, CytoJournal.

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

[18]  A. Banito,et al.  Aneuploidy and RAS mutations are mutually exclusive events in the development of well‐differentiated thyroid follicular tumours , 2007, Clinical endocrinology.

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

[20]  Pei-Wen Wang,et al.  Selective occurrence of ras mutations in benign and malignant thyroid follicular neoplasms in Taiwan. , 2004, Thyroid : official journal of the American Thyroid Association.

[21]  Z. Baloch,et al.  Fine-needle aspiration of thyroid nodules: past, present, and future. , 2004, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[22]  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.

[23]  V. Vasko,et al.  Specific pattern of RAS oncogene mutations in follicular thyroid tumors. , 2003, The Journal of clinical endocrinology and metabolism.

[24]  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.

[25]  A. Oberg,et al.  Papillary Thyroid Carcinoma Managed at the Mayo Clinic during Six Decades (1940–1999): Temporal Trends in Initial Therapy and Long-term Outcome in 2444 Consecutively Treated Patients , 2002, World Journal of Surgery.

[26]  M. Safran,et al.  Follicular variant of papillary thyroid carcinoma: a comparative study of histopathologic features and cytology results in 141 patients. , 2001, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[27]  J. Fagin,et al.  The RAS oncogene induces genomic instability in thyroid PCCL3 cells via the MAPK pathway , 2000, Oncogene.

[28]  D. Rimm,et al.  Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma. , 1999, Cancer research.

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

[30]  C. Ledent,et al.  Thyroid pathologies in transgenic mice expressing a human activated Ras gene driven by a thyroglobulin promoter. , 1996, Oncogene.

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

[32]  R. Davis,et al.  The mitogen-activated protein kinase signal transduction pathway. , 1993, The Journal of biological chemistry.

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

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

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

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

[37]  W. Kabsch,et al.  Structure of the guanine-nucleotide-binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation , 1989, Nature.

[38]  Joyce Bos.  ras oncogenes in human cancer: a review. , 1989, Cancer research.

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

[40]  B. Caillou,et al.  Detection of activated ras oncogenes in human thyroid carcinomas. , 1988, Oncogene.

[41]  J. Rosai,et al.  Papillary carcinoma of the thyroid. A discussion of its several morphologic expressions, with particular emphasis on the follicular variant. , 1983, The American journal of surgical pathology.

[42]  O. Clark,et al.  Significance of lymph node metastasis in differentiated thyroid cancer. , 1978, American journal of surgery.

[43]  E. Mazzaferri.  Increasing Incidence of Thyroid Cancer in the United States, 1973–2002Davies L, Welch HG (Dept of Veterans Affairs Med Ctr, White River Junction, Vt; Darmouth Med School, Hanover, NH) JAMA 295:2164–2167, 2006§ , 2007 .

[44]  R. DeLellis.  Pathology and genetics of tumours of endocrine organs , 2004 .

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

[46]  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.

[47]  J. Bond,et al.  In vitro reconstruction of tumour initiation in a human epithelium. , 1994, Oncogene.

[48]  J. Fagin,et al.  High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. , 1993, The Journal of clinical investigation.

[49]  L. Davies,et al.  Increasing incidence of thyroid cancer in the United States, 1973-2002. , 2006, JAMA.