Follicular cell (papillary and follicular) thyroid carcinoma, genetic inheritance, and molecular diagnostic markers

Kazubskaya T.P.; Kozlova V.M.; Kondrat'eva T.T.; Pavlovskaya A.I.; Marakhonov A.V.; Baranova A.V.; Ivanova N.I.; Stepanova A.A.; Poliakov A.V.; Belev N.F.; Brzhezovsky V.Zh.

doi:https://doi.org/

Kazubskaya T.P.

N.N. Blokhin Russian Cancer Research Center, Moscow, Russia

Kozlova V.M.

N.N. Blokhin Russian Cancer Research Center, Moscow, Russia;
Research Centre for Medical Genetics, Moscow, Russia

Kondrat'eva T.T.

FGBU "Moskovskiĭ onkologicheskiĭ nauchnyĭ tsentr im. N.N. Blokhina" RAMN, Moskva

Pavlovskaya A.I.

N.N. Blokhin Russian Cancer Research Center, Moscow, Russia

Marakhonov A.V.

FGBU "Meditsinskiĭ geneticheskiĭ nauchnyĭ tsentr" RAMN, Moskva

Baranova A.V.

FGBU "Meditsinskiĭ geneticheskiĭ nauchnyĭ tsentr" RAMN, Moskva

Ivanova N.I.

Kafedra otorinolaringologii

Stepanova A.A.

FGBU "Meditsinskiĭ geneticheskiĭ nauchnyĭ tsentr" RAMN, Moskva

Poliakov A.V.

Mediko-geneticheskiĭ nauchnyĭ tsentr RAMN, Moskva

Belev N.F.

Institut onkologii Moldovy, Kishinev

Brzhezovsky V.Zh.

N.N. Blokhin Russian Cancer Research Center, Moscow, Russia

Follicular cell (papillary and follicular) thyroid carcinoma, genetic inheritance, and molecular diagnostic markers

Authors:

Kazubskaya T.P., Kozlova V.M., Kondrat'eva T.T., Pavlovskaya A.I., Marakhonov A.V., Baranova A.V., Ivanova N.I., Stepanova A.A., Poliakov A.V., Belev N.F., Brzhezovsky V.Zh.

More about the authors

Journal: Russian Journal of Archive of Pathology. 2014;76(5): 3‑12

Read: 8591 times

Download PDF (RU)

Contact the author

Table of contents

To cite this article:

Kazubskaya TP, Kozlova VM, Kondrat'eva TT, et al. . Follicular cell (papillary and follicular) thyroid carcinoma, genetic inheritance, and molecular diagnostic markers. Russian Journal of Archive of Pathology. 2014;76(5):3‑12. (In Russ.)

Подписка 2026 Архив патологии (Russian Journal of Archive of Pathology)

Использование инфографики авторами научных работ

Close metadata

Abstract:

Objective - to determine the genetic forms of follicular cell thyroid carcinoma (FCTC) (papillary and follicular thyroid carcinoma (PTC and FTC)), to identify criteria to individually predict the development of the same disease for relatives, and to assess the role of molecular markers in the diagnosis, prognosis, and treatment of this disease. Subjects and methods. One hundred and ninety adult patients aged 20 to 84 years with histologically verified PTC and FTC and 20 children (12 patients with PTC and 8 with benign thyroid tumors) aged 2 to 16 years were examined. To assess the role of the BRAF gene as a molecular marker for thyroid carcinoma, DNA was isolated from the thyroid tumor tissue of 29 patients, which had been obtained by fine-needle aspiration biopsy (FNAB) and scraping and swabbing the cytological specimen previously showing an area containing tumor cells. A BRAF с.1799Т>А (р.V600E) mutation in the FNAB specimens was tested by allele-specific ligation, followed by PCR amplification. Results. The examinees' families were found to have a segregation of benign thyroid tumor and nontumor diseases (13.6%). Neoplasias of different sites were observed in 15% of the patients' relatives. Multiple primary tumors were detected in 6.1% of the patients and in 25% of the examined children (3/12). PTC was ascertained to accumulate as two clinical forms in the families. One form belongs to familial PTC (FPTC) in which two or three generations of relatives in the family are afflicted by only PTC and have a more severe phenotype of the disease. The other includes an association of FPTC with papillary kidney cancer. Furthermore, FPTC and PTC may be a component of multitumor syndromes, such as multiple endocrine neoplasia type 1, Cowden syndrome, and familial adenomatous polyposis. The familial hereditary forms of FCTC were generally revealed in 4.2% of the patients. BRAF v600E mutations were found in only 3 patients with Stages II and III PTC and were not in all the 12 children with PTC. Conclusion. The found clinical manifestation of the hereditary forms of FCTC permits the identification of people at high risk for this disease. No correlation between somatic BRAF mutations with a less favorable course in PTC can be noticed because there are few observations. Analysis of published data on the role of molecular markers in FCTC has shown that the existing specific somatic changes complement information in the differential cytological diagnosis when examining FNAB specimens.

Keywords:

papillary and follicular thyroid carcinoma

hereditary forms

molecular and genetic markers

Authors:

Kazubskaya T.P.

N.N. Blokhin Russian Cancer Research Center, Moscow, Russia

Kozlova V.M.

N.N. Blokhin Russian Cancer Research Center, Moscow, Russia;
Research Centre for Medical Genetics, Moscow, Russia

Kondrat'eva T.T.

FGBU "Moskovskiĭ onkologicheskiĭ nauchnyĭ tsentr im. N.N. Blokhina" RAMN, Moskva

Pavlovskaya A.I.

N.N. Blokhin Russian Cancer Research Center, Moscow, Russia

Marakhonov A.V.

FGBU "Meditsinskiĭ geneticheskiĭ nauchnyĭ tsentr" RAMN, Moskva

Baranova A.V.

FGBU "Meditsinskiĭ geneticheskiĭ nauchnyĭ tsentr" RAMN, Moskva

Ivanova N.I.

Kafedra otorinolaringologii

Stepanova A.A.

FGBU "Meditsinskiĭ geneticheskiĭ nauchnyĭ tsentr" RAMN, Moskva

Poliakov A.V.

Mediko-geneticheskiĭ nauchnyĭ tsentr RAMN, Moskva

Belev N.F.

Institut onkologii Moldovy, Kishinev

Brzhezovsky V.Zh.

N.N. Blokhin Russian Cancer Research Center, Moscow, Russia

Close metadata

References:

Davydov M.I., Aksel' E.M. Morbidity of malignant neoplasms. Vestnik RONTs im. N.N. Blokhina RAMN. 2011; 22: 54-165. (In Russ.)
Kondo T., Ezzat S., Asa S.L. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat. Rev. Cancer. 2006; 6: 292-306.
Shibru D., Hwang J., Khanafshar E., Duh Q.Y., Clark O.H., Kebebew E. Does the 3-gene diagnostic assay accurately distinguish benign from malignant thyroid neoplasms? Cancer. 2008; 113 (5): 930-5.
Grossman R.F., Tu S.H., Duh Q.Y., Siperstein AE., Novosolov F., Clark O.H. Familial nonmedullary thyroid cancer. An emerging entity that warrants aggressive treatment. Arch. Surg. 1995; 130: 892-7.
Goldgar D.E., Easton D.F., Cannon-Albright L.A. et al. Systematic populationbased assessment of cancer risk in first-degree relatives of cancer probands. J. Natl. Cancer Inst. 1994; 86: 1600-8.
Pal T., Vogl F.D., Chappuis P.O. et al. Increased risk for nonmedullary thyroid cancer in the first degree relatives of prevalent cases of nonmedullary т thyroid cancer: a hospital-based study. J. Clin. Endocrinol. Metab. 2001; 86: 5307-12.
Landa I., Robledo M. Association stidies in thyroid cancer susceptibility: are we on the right track? J. Mol. Endocrinol. 2011; 47: R43-58.
Malchoff C., Malchoff D. The genetics of hereditary nonmedullary thyroid carcinoma. J. Clin. Endocrinol. Metab. 2002; 87 (6): 2455-9.
Adjadj E., Rubino C., Shamsaldim A. et al. The risk of multiple primary breast and thyroid carcinomas. Cancer. 2003; 98: 1309-17.
Canchola A.J., Horn-Ross P.L., Purdie D.M. Risk of second primary malignancies in women with papillary thyroid cancer. Am. J. Epidemiol. 2006; 163 (6): 521-7.
Chen A.Y., Levy L. et al. The development of breast carcinoma in woman with thyroid carcinoma. Cancer. 2001; 92 (2): 225-31.
Matsuo K., Tang S.H., Fagin J.A. Allelotype of human thyroid tumors: loss of chromosome 11q13 sequences in follicular neoplasms. Mol. Endocrinol. 1991; 5: 1873-9.
Marx S.J. Multiple endocrine neoplasia type 1. In : Kinzler KW,ed. The genetic basis of human cancer. 2nd ed. NewYork: McGraw Hill; 2002: 475-500.
Maehama T., Dixon J.E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-triphosphate. J. Biol. Chem. 1998; 273 (22): 13375-8.
Nelen M.R., van Staveren W.C., Peeters E.A., Hassel M.B. et al. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum. Mol. Genet. 1997; 6 (8): 1383-7.
Li L., Liu F., Ross A.H. PTEN regulation of neural development and CNS stem cells. J. Cell. Biochem. 2003; 88: 24-8.
Konopka B., Paszko Z., Janiec-Jankowska A., Goluda M. Assessment of the quality and frequency of mutations occurrence in PTEN gene in endometrial carcinomas and hyperplasis. Cancer Lett. 2002; 178: 43-5113.
Reifenberger J., Wolter M., Bostrom J. et al. Allelic losses on chromosome arm 10q and mutation of the PTEN(MMAC1) tumor supressor gene in primary and metastaticmalignant melanomas. Virchev Arch. 2000; 436: 487-93.
Berger M.F., Hodis E., Heffernan T.P., Deribe Y.L., Lawrence M.S., Protopopov A. et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 2012; 485 (7399): 502-6.
Cetta F., Montalto G., Gori M., Curia M.C., Cama A., Olschwang S. Germline mutations of the APC gene in patients with familial adenomatous polyposis-associated thyroid carcinoma: results from a European cooperative study. J. Clin. Endocrinol. Metab. 2000; 85 (1): 286-92.
Soravia C., Sugg S.L., Berk T. et al. Familial adenomatous polyposis-associated thyroid cancer. Am. J. Pathol. 1999; 154: 127-135.
Kinzler K.W., Nilbert M.C., Su N.K. Identification of FAP locus genes from chromosome 5q21. Science. 1991; 253: 661-4.
Santoro M., Thomas G.A., Vecchio G., Williams G.H. et al. Gene rearrangement and Chernobyl related thyroid cancers. Br. J. Cancer. 2000; 82 (2): 315-22.
Nikiforov Y.E. RET/PTC rearrangement in thyroid tumors. Endocr. Pathol. 2002; 13: 3-16.
Baloch Z.W., Livolsi V.A. Pathologic diagnosis of papillary thyroid carcinoma: today and tomorrow. Expert Rev. Mol. Diagn. 2005; 5: 573-84.
Ishizaka Y., Kobayashi S., Ushijima T., Hirohashi S., Sugimura T., Nagao M. Detection of retTPC/PTC transcripts in thyroid adenomas and adenomatous goiter by an RT-PCR method. Oncogene. 1991; 6 (9): 1667-72.
Tallini G., Asa S.L. RET oncogene activation in papillary thyroid carcinoma. Adv. Anat. Pathol. 2001; 8 (6): 345-54.
Ishizaka Y., Kobayashi S., Ushijima T., Hirohashi S., Sugimura T., Nagao M. Detection of retTPC/PTC transcripts in thyroid adenomas and adenomatous goiter by an RT-PCR method. Oncogene. 1991; 6 (9): 1667-72.
Nikiforov Y.E., Rowland J.M., Bove K.E., Monforte-Munoz H., Fagin J.A. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res. 1997; 57 (9): 1690-4.
Adeniran A.J., Zhu Z., Gandhi M., Steward D.L., Fidler J.P., Giordano T.J. et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am. J. Surg. Pathol. 2006; 30 (2): 216-22.
Garcia-Rostan G., Zhao H., Camp R.L., Pollan M., Herrero A., Pardo J. et al. Ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J. Clin. Oncol. 2003; 21 (17): 3226.
Zhu Z., Ciampi R., Nikiforova M.N., Gandhi M., Nikiforov Y.E. Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity. J. Clin. Endocrinol. Metab. 2006; 91 (9): 3603-10.
Xing M. BRAF mutation in thyroid cancer. Endocr. Relat. Cancer. 2005; 12 (2): 245-62.
Ciampi R., Knauf J., Kerler R. et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J. Clin. Invest. 2005; 115: 94-101.
Davies H., Bignell G.R., Cox C. et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417: 949-54.Ball D.W. Selectively targeting mutant BRAF in thyroid cancer. J. Clin. Endocrinol. Metab. 2010; 95: 60-1.
Nikiforova M.N, Nikiforov Y.E. Molecular diagnostics and predictors in thyroid cancer. Thyroid. 2009; 19 (12): 1351-61.
Jo Y.S., Huang S., Kim Y.J., Lee I.S., Kim S.S. et al. Diagnostic value of pyrosequencing for the BRAF V600E mutation in ultrasound-guided fine-needle aspiration biopsy samples of thyroid incidentaloma. Clin. Endocrinol. (Oxf). 2009; 70 (1): 139-44.
Kim T.H., Park Y.J., Lim J.A. et al. The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer. 2012; 118: 1764-73.
Kim T.H., Park Y.J., Lim J.A. et al. The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer. 2012; 118: 1764-73.
Nam J.K., Jung C.K., Song B.J., Lim D.J., Chae B.J., Lee N.S. et al. Is the BRAF(V600E) mutation useful as a predictor of preoperative risk in papillary thyroid cancer? Am. J. Surg. 2012; 203 (4): 436-41.
Cohen Y., Xing M., Mambo E., Guo Z., Wu G., Trink B. et al. BRAF mutation in papillary thyroid carcinoma. J. Natl. Cancer Inst. 2003; 95 (8): 625-7.
Xing M., Alzahrani A.S., Carson K.A., Viola D., Elisei R., Bendlova B. et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA. 2013; 309 (14): 1493-501.
Nikiforova M.N., Nikiforov Y.E. Molecular diagnostics and predictors in thyroid cancer. Thyroid. 2009; 19 (12): 1351-61.
Soares P., Sobrinho-Simões M. Cancer: Small papillary thyroid cancers - is BRAF of prognostic value? Nat. Rev. Endocrinol. 2011; 7 (1): 9-10.
Lemoine N.R., Mayall E.S., Wyllie F.S., Williams E.D. et al. High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene. 1989; 4 (2): 159-64.
French C.A., Alexander E.K., Cibas E.S., Nose V., Laguette J. et al. Genetic and biological subgroups of low-stage follicular thyroid cancer. Am. J. Pathol. 2003; 162 (4): 1053-60.
Fukahori M., Yoshida A., Hayashi H. et al. The association between RAS gene mutations and clinical characteristics in follicular thyroid tumors: new insights from a single center and a large patient cohort. Thyroid. 2012; 22: 683-9.
Basolo F., Pisaturo F., Pollina L.E. еt al. N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression. Thyroid. 2000; 10 (1): 19-24.
Namba H., Rubin S.A., Fagin J.A. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol. Endocrinol. 1990: 4 (10): 1474-9.
Kroll T.G., Sarraf P., Pecciarini L., Chen C.J., Mueller E., Spiegelman B.M., Fletcher J.A. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma. Science. 2000; 289 (5483): 1357-60.
Ying H., Suzuki H., Zhao L., Willingham M.C., Meltzer P., Cheng S.Y. Mutant thyroid hormone receptor beta represses the expression and transcriptional activity of peroxisome proliferator-activated receptor gamma during thyroid carcinogenesis. Cancer Res. 2003; 63 (17): 5274-80.
Nikiforova M.N., Lynch R.A., Biddinger P.W. et al. RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J. Clin. Endocrinol. Metab. 2003; 88: 2318-26.
Dwight T., Thoppe S.R., Foukakis T., Lui W.O., Wallin G., Höög A. et al. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J. Clin. Endocrinol. Metab. 2003; 88 (9): 4440-5.
Castro P., Rebocho A.P., Soares R.J., Magalhães J., Roque L. et al. PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 2006; 91 (1): 213-20.
Marques A.R., Espadinha C., Catarino A.L., Moniz S., Pereira T., Sobrinho L.G., Leite V. Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas. Clin. Endocrinol. Metab. 2002; 87 (8): 3947-5276.
Nikiforov Y.E., Steward D.L, Robinson-Smith T.M., Haugen B.R., Klopper J.P, Zhu Z. et al. Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules J. Clin. Endocrinol. Metab. 2009; 94: 2092-8.
Cantara S., Capezzone M., Marchisotta S., Capuano S. et al. Impact of proto-oncogene mutation detection in cytological specimens from thyroid nodules improves the diagnostic accuracy of cytology. J. Clin. Endocrinol. Metab. 2010; 95: 1365-9.
Rousset B. Molecular diagnosis of differentiated thyroid cancer. Towards the application in clinical practice. Ann. Endocrinol. (Paris). 2008; 69 (2): 135-7.
Pizzolanti G., Russo L., Richiusa P. et al. Fine-needle aspiration molecular analysis for the diagnosis of papillary thyroid carcinoma through BRAF V600E mutation and RET/PTC rearrangement. Thyroid. 2007; 17 (11): 1109-15.