Analysis of Clonal Origin of Thyroid Nodules_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

SONG Turun ^1,2 , LIAO Banghua ^1,2 , WEN Lebin ¹ , LI Zhihui. ¹

1. Department of Thyroid and Breast Surgery， West China Hospital， Sichuan University， Chengdu 610041， Sichuan Province， China;;
2. West China Medical School， Sichuan University， Chengdu 610041， Sichuan Province， China;

Corresponding author：

Keywords：

Thyroid nodule; Thyroid tumor; X chromosome inactivation; Single gene mutation

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Objective 　To further strengthen the understanding of the genesis of thyroid tumors through the analysis of thyroid nodules in the clonal origin.
Method 　The related literatures which discussed the clonality of thyroid nodules were reviewed and analyzed.
Results 　About the clonal origin of thyroid nodules， the X chromosome inactivation detection and single gene mutation detection were the most widely chosen one at present. Most of the materials available at present related to X chromosome inactivation proposed that major part of the thyroid nodules were monoclonal and the malignant cells spreaded by means of the inner lymphatic vessel net，whereas polyclonal and monoclonal thyroid nodules coexisted occasionally. Only BRAF mutation was found of certain importance in clonal origin identification in the thyroid nodules.
Conclusions 　Thyroid nodule is prevalent in clinical practice，while the clonality of thyroid nodules especially the thyroid tumor is not clear. And for the time being the commonly used methods to identify the clonal origin of thyroid nodule are X chromosome inactivation and single gene mutation detection. Published results confirm the finding of X chromosome inactivation methods that the majority of thyroid nodules are monoclonally originated.

Citation： SONG Turun,LIAO Banghua,WEN Lebin,LI Zhihui.. Analysis of Clonal Origin of Thyroid Nodules. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2012, 19(8): 899-903. doi: Copy

1.	Cooper DS， Doherty GM， Haugen BR， et al. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer[J]. Thyroid， 2009， 19(11)：1167-1214.
2.	Moniz S， Catarino AL， Marques AR， et al. Clonal origin of non-medullary thyroid tumours assessed by non-random X-chromosome inactivation[J]. Eur J Endocrinol， 2002， 146(1)：27-33.
3.	Shattuck TM， Westra WH， Ladenson PW， et al. Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma[J]. N Engl J Med， 2005， 352(23)：2406-2412.
4.	Kopp P， Kimura ET， Aeschimann S， et al. Polyclonal and monoclonal thyroid nodules coexist within human multinodular goiters[J]. J Clin Endocrinol Metab， 1994， 79(1)：134-139.
5.	樊洁，唐峰，包芸，等. 甲状腺多结节性增生的克隆性分析[J]. 临床与实验病理学杂志， 2007， 23(4)：395-399.
6.	Moon HJ， Kwak JY， Kim EK， et al. The role of BRAFV600E mutation and ultrasonography for the surgical management of a thyroid nodule suspicious for papillary thyroid carcinoma on cytology[J]. Ann Surg Oncol， 2009， 16(11)：3125-3131.
7.	Lyon MF. Gene action in the X-chromosome of the mouse (Mus musculus L)[J]. Nature， 1961， 190：372-373.
8.	Lock LF， Takagi N， Martin GR. Methylation of the Hprt gene on the inactive X occurs after chromosome inactivation[J]. Cell， 1987， 48(1)：39-46.
9.	Fey MF， Liechti-Gallati S， von Rohr A， et al. Clonality andX-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe[J]. Blood， 1994， 83(4)：931-938.
10.	Allen RC， Nachtman RG， Rosenblatt HM， et al. Application of carrier testing to genetic counseling for X-linked agammaglobulinemia[J]. Am J Hum Genet， 1994， 54(1)：25-35.
11.	Belmont JW. Genetic control of X inactivation and processes leading to X-inactivation skewing[J]. J Hum Genet， 1996， 58(6)：1101-1108.
12.	Hatakeyama C， Anderson CL， Beever CL， et al. The dynamics of X-inactivation skewing as women age[J]. Clin Genet， 2004， 66(4)：327-332.
13.	李刚，苏勤，张伟，等．中国女性血细胞X染色体失活偏移与年龄相关[J]. 现代肿瘤医学， 2006， 14(3)：266-269.
14.	Sharp A， Robinson D， Jacobs P. Age- and tissue-specific variation of X chromosome inactivation ratios in normal women[J]. Hum Genet， 2000， 107(4)：343-349.
15.	李刚，苏勤，刘贵秋，等. 女性血细胞X染色体失活偏移与肺癌早期发生有关[J]. 中华肿瘤杂志， 2006， 28(9)：666-669.
16.	Simmonds M， Newby P， Jackson L， et al. Further evidence of a role for X chromosome inactivation contributing to the female preponderance of Graves’ disease [J]. Thyroid， 2009， 19(s1)：S-21-S-93.
17.	李刚. 血细胞X染色体失活偏移与女性肺癌、食管癌的早期发生有关[D]. 第四军医大学， 2006：1-62.
18.	Boggs BA， Chinault AC. Analysis of replication timing properties of human X-chromosomal loci by fluorescence in situ hybridization[J]. Proc Natl Acad Sci USA， 1994， 91(13)：6083-6087.
19.	Gartler SM， Gandini E， Angioni G， et al. Glucose-6 phosphate dehydrogenase mosaicism：utilization as a tracer in the study of the development of hair root cells[J]. Ann Hum Genet， 1969， 33(2)：171-176.
20.	Boyd Y， Fraser NJ. Methylation patterns at the hypervariable X-chromosome locus DXS255 (M27 beta)：correlation withX-inactivation status[J]. Genomics， 1990， 7(2)：182-187.
21.	Allen RC， Zoghbi HY， Moseley AB， et al. Methylation of HpaⅡ and HhaⅠ sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation[J]. Am J Hum Genet， 1992， 51(6)：1229-1239.
22.	Lavin VA， Hamid R， Patterson J， et al. Use of human androgen receptor gene analysis to aid the diagnosis of JMML in female noonan syndrome patients[J]. Pediatr Blood Cancer， 2008， 51(2)：298-302.
23.	Apel RL， Ezzat S， Bapat BV， et al. Clonality of thyroid nodules in sporadic goiter[J]. Diagn Mol Pathol， 1995， 4(2)：113-121.
24.	Aeschimann S， Kopp PA， Kimura ET， et al. Morphological and functional polymorphism within clonal thyroid nodules[J]. J Clin Endocrinol Metab， 1993， 77(3)：846-851.
25.	Derwahl M. Molecular aspects in the pathogenesis of nodules and adenomas of the thyroid gland[J]. Schweiz Med Wochenschr， 1994， 124(37)：1613-1618.
26.	Gerber H， Bürgi U， Peter HJ. Etiology and pathogenesis of thyroid nodules [J]. Exp Clin Endocrinol， 1993， 101：97–101.
27.	Harrer P， Broecker M， Zint A， et al．Thyroid nodules in recurrent multinodular goiters are predominantly polyclonal[J]. J Endocrinol Invest， 1998， 21(6)：380-385.
28.	Fialkow PJ. Clonal origin of human tumors[J]. Annu Rev Med， 1976， 458(3)：283-321.
29.	Namba H， Matsuo K， Fagin JA. Clonal composition of benign and malignant human thyroid tumors[J]. J Clin Invest， 1990， 86(1)：120-125.
30.	Wang W， Wang H， Teng X， et al. Clonal analysis of bilateral， recurrent， and metastatic papillary thyroid carcinomas[J]. Hum Pathol， 2010， 41(9)：1299-1309.
31.	McCarthy RP， Wang M， Jones TD， et al. Molecular evidence for the same clonal origin of multifocal papillary thyroid carcinomas[J]. Clin Cancer Res， 2006， 12(8)：2414-2418.
32.	Kim H， Piao Z， Park C， et al. Clinical significance of clonality in thyroid nodules[J]. Br J Surg， 1998， 85(8)：1125-1128.
33.	Ferraris AM， Mangerini R， Gaetani GF， et al. Polyclonal origin of medullary carcinoma of the thyroid in multiple endocrine neoplasia type 2[J]. Hum Genet， 1997， 99(2)：202-205.
34.	Marques AR， Catarino AL， Moniz S， et al. Medullary carcinomas of the thyroid：a monoclonal origin[J]. Thyroid， 2001， 11(12)：1109-1113.
35.	Rienhoff WF Jr. The lymphatic vessels of the thyroid gland in the dog and in man[J]. Arch Surg， 1931， 23(5)：783-804.
36.	Iida F， Yonekura M， Miyakawa M. Study of intraglandular dissemination of thyroid cancer[J]. Cancer， 1969， 24(4)：764-771.
37.	Diallo R， Schaefer KL， Poremba C， et al. Monoclonality in normal epithelium and in hyperplastic and neoplastic lesions of the breast[J]. J Pathol， 2001， 193(1)：27-32.
38.	Li M， Cordon-Cardo C， Gerald WL， et al. Desmoid fibromatosis is a clonal process[J]. Hum Pathol， 1996， 27(9)：939-943.
39.	Jovanovic L， Delahunt B， Mciver B， et al. Thyroid gland clonality revisited：the embryonal patch size of the normal human thyroid gland is very large， suggesting X-chromosome inactivation tumor clonality studies of thyroid tumors have to be interpreted with caution[J]. J Clin Endocrinol Metab， 2003， 88(7)：3284-3291.
40.	Riesco-Eizaguirre G， Santisteban P. Molecular biology of thyroid cancer initiation[J]. Clin Transl Oncol， 2007， 9(11)：686-693.
41.	Kondo T， Ezzat S， Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia[J]. Nat Rev Cancer， 2006， 6(4)：292-306.
42.	Xing M. BRAF mutation in thyroid cancer[J]. Endocr Relat Cancer， 2005， 12(2)：245-262.
43.	Lee X， Gao M， Ji Y， et al. Analysis of differential BRAFV600E mutational status in high aggressive papillary thyroid microcarcinoma[J]. Ann Surg Oncol， 2009， 16(2)：240-245.
44.	Park SY， Park YJ， Lee YJ， et al. Analysis of differential BRAFV600E mutational status in multifocal papillary thyroid carcinoma：evidence of independent clonal origin in distinct tumor foci[J]. Cancer， 2006， 107(8)：1831-1838.
45.	Giannini R， Ugolini C， Lupi C， et al. The heterogeneous distribution of BRAF mutation supports the independent clonal origin of distinct tumor foci in multifocal papillary thyroid carcinoma[J]. J Clin Endocrinol Metab， 2007， 92(9)：3511-3516.
46.	Jovanovic L， Delahunt B， Mciver B， et al. Most multifocal papillary thyroid carcinomas acquire genetic and morphotype diversity through subclonal evolution following the intra-glandular spread of the initial neoplastic clone[J]. J Pathol， 2008， 215(2)：145-154.
47.	Segev DL， Umbricht C， Zeiger MA. Molecular pathogenesis of thyroid cancer[J]. Surg Oncol， 2003， 12(2）：69-90.
48.	Cheung CC， Carydis B， Ezzat S， et al. Analysis of ret/PTC gene rearrangements refines the fine needle aspiration diagnosis of thyroid cancer[J]. J Clin Endocrinol Metab， 2001， 86(5)：2187-2190.
49.	Unger K，Zitzelsberger H， Salvatore G， et al. Heterogeneity in the distribution of RET/PTC rearrangements within individual post-chernobyl papillary thyroid carcinomas[J]. J Clin Endocrinol Metab， 2004， 89(9)：4272-4279.
50.	Santoro M， Melillo RM， Fusco A. RET/PTC activation in papillary thyroid carcinoma：European Journal of Endocrinology Prize Lecture[J]. Eur J Endocrinol， 2006， 155(5)：645-653.
51.	Fusco A， Chiappetta G， Hui P， et al. Assessment of RET/PTC oncogene activation and clonality in thyroid nodules with incomplete morphological evidence of papillary carcinoma：a search for the early precursors of papillary cancer[J]. Am J Pathol， 2002， 160(6)：2157-2167.
52.	Garcia-Rostan G， Zhao H， Camp RL， et al. ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer[J]. J Clin Oncol. 2003， 21(17)：3226-3235.
53.	Nikiforov YE， Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer [J]. Nat Rev Endocrinol， 2011，7(10)：569-580．.
54.	Donghi R， Longoni A， Pilotti S， et al. Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland[J]. J Clin Invest， 1993， 91(4)：1753-1760.
55.	Ito T， Seyama T， Mizuno T， et al. Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland[J]. Cancer Res， 1992，52(5)：1369-1371.

1. 　 Cooper DS， Doherty GM， Haugen BR， et al. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer[J]. Thyroid， 2009， 19(11)：1167-1214.
2. Moniz S， Catarino AL， Marques AR， et al. Clonal origin of non-medullary thyroid tumours assessed by non-random X-chromosome inactivation[J]. Eur J Endocrinol， 2002， 146(1)：27-33.
3. Shattuck TM， Westra WH， Ladenson PW， et al. Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma[J]. N Engl J Med， 2005， 352(23)：2406-2412.
4. Kopp P， Kimura ET， Aeschimann S， et al. Polyclonal and monoclonal thyroid nodules coexist within human multinodular goiters[J]. J Clin Endocrinol Metab， 1994， 79(1)：134-139.
5. 樊洁，唐峰，包芸，等. 甲状腺多结节性增生的克隆性分析[J]. 临床与实验病理学杂志， 2007， 23(4)：395-399.
6. Moon HJ， Kwak JY， Kim EK， et al. The role of BRAFV600E mutation and ultrasonography for the surgical management of a thyroid nodule suspicious for papillary thyroid carcinoma on cytology[J]. Ann Surg Oncol， 2009， 16(11)：3125-3131.
7. Lyon MF. Gene action in the X-chromosome of the mouse (Mus musculus L)[J]. Nature， 1961， 190：372-373.
8. Lock LF， Takagi N， Martin GR. Methylation of the Hprt gene on the inactive X occurs after chromosome inactivation[J]. Cell， 1987， 48(1)：39-46.
9. Fey MF， Liechti-Gallati S， von Rohr A， et al. Clonality andX-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe[J]. Blood， 1994， 83(4)：931-938.
10. Allen RC， Nachtman RG， Rosenblatt HM， et al. Application of carrier testing to genetic counseling for X-linked agammaglobulinemia[J]. Am J Hum Genet， 1994， 54(1)：25-35.
11. Belmont JW. Genetic control of X inactivation and processes leading to X-inactivation skewing[J]. J Hum Genet， 1996， 58(6)：1101-1108.
12. Hatakeyama C， Anderson CL， Beever CL， et al. The dynamics of X-inactivation skewing as women age[J]. Clin Genet， 2004， 66(4)：327-332.
13. 李刚，苏勤，张伟，等．中国女性血细胞X染色体失活偏移与年龄相关[J]. 现代肿瘤医学， 2006， 14(3)：266-269.
14. Sharp A， Robinson D， Jacobs P. Age- and tissue-specific variation of X chromosome inactivation ratios in normal women[J]. Hum Genet， 2000， 107(4)：343-349.
15. 李刚，苏勤，刘贵秋，等. 女性血细胞X染色体失活偏移与肺癌早期发生有关[J]. 中华肿瘤杂志， 2006， 28(9)：666-669.
16. Simmonds M， Newby P， Jackson L， et al. Further evidence of a role for X chromosome inactivation contributing to the female preponderance of Graves’ disease [J]. Thyroid， 2009， 19(s1)：S-21-S-93.
17. 李刚. 血细胞X染色体失活偏移与女性肺癌、食管癌的早期发生有关[D]. 第四军医大学， 2006：1-62.
18. Boggs BA， Chinault AC. Analysis of replication timing properties of human X-chromosomal loci by fluorescence in situ hybridization[J]. Proc Natl Acad Sci USA， 1994， 91(13)：6083-6087.
19. Gartler SM， Gandini E， Angioni G， et al. Glucose-6 phosphate dehydrogenase mosaicism：utilization as a tracer in the study of the development of hair root cells[J]. Ann Hum Genet， 1969， 33(2)：171-176.
20. Boyd Y， Fraser NJ. Methylation patterns at the hypervariable X-chromosome locus DXS255 (M27 beta)：correlation withX-inactivation status[J]. Genomics， 1990， 7(2)：182-187.
21. Allen RC， Zoghbi HY， Moseley AB， et al. Methylation of HpaⅡ and HhaⅠ sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation[J]. Am J Hum Genet， 1992， 51(6)：1229-1239.
22. Lavin VA， Hamid R， Patterson J， et al. Use of human androgen receptor gene analysis to aid the diagnosis of JMML in female noonan syndrome patients[J]. Pediatr Blood Cancer， 2008， 51(2)：298-302.
23. Apel RL， Ezzat S， Bapat BV， et al. Clonality of thyroid nodules in sporadic goiter[J]. Diagn Mol Pathol， 1995， 4(2)：113-121.
24. Aeschimann S， Kopp PA， Kimura ET， et al. Morphological and functional polymorphism within clonal thyroid nodules[J]. J Clin Endocrinol Metab， 1993， 77(3)：846-851.
25. Derwahl M. Molecular aspects in the pathogenesis of nodules and adenomas of the thyroid gland[J]. Schweiz Med Wochenschr， 1994， 124(37)：1613-1618.
26. Gerber H， Bürgi U， Peter HJ. Etiology and pathogenesis of thyroid nodules [J]. Exp Clin Endocrinol， 1993， 101：97–101.
27. Harrer P， Broecker M， Zint A， et al．Thyroid nodules in recurrent multinodular goiters are predominantly polyclonal[J]. J Endocrinol Invest， 1998， 21(6)：380-385.
28. Fialkow PJ. Clonal origin of human tumors[J]. Annu Rev Med， 1976， 458(3)：283-321.
29. Namba H， Matsuo K， Fagin JA. Clonal composition of benign and malignant human thyroid tumors[J]. J Clin Invest， 1990， 86(1)：120-125.
30. Wang W， Wang H， Teng X， et al. Clonal analysis of bilateral， recurrent， and metastatic papillary thyroid carcinomas[J]. Hum Pathol， 2010， 41(9)：1299-1309.
31. McCarthy RP， Wang M， Jones TD， et al. Molecular evidence for the same clonal origin of multifocal papillary thyroid carcinomas[J]. Clin Cancer Res， 2006， 12(8)：2414-2418.
32. Kim H， Piao Z， Park C， et al. Clinical significance of clonality in thyroid nodules[J]. Br J Surg， 1998， 85(8)：1125-1128.
33. Ferraris AM， Mangerini R， Gaetani GF， et al. Polyclonal origin of medullary carcinoma of the thyroid in multiple endocrine neoplasia type 2[J]. Hum Genet， 1997， 99(2)：202-205.
34. Marques AR， Catarino AL， Moniz S， et al. Medullary carcinomas of the thyroid：a monoclonal origin[J]. Thyroid， 2001， 11(12)：1109-1113.
35. Rienhoff WF Jr. The lymphatic vessels of the thyroid gland in the dog and in man[J]. Arch Surg， 1931， 23(5)：783-804.
36. Iida F， Yonekura M， Miyakawa M. Study of intraglandular dissemination of thyroid cancer[J]. Cancer， 1969， 24(4)：764-771.
37. Diallo R， Schaefer KL， Poremba C， et al. Monoclonality in normal epithelium and in hyperplastic and neoplastic lesions of the breast[J]. J Pathol， 2001， 193(1)：27-32.
38. Li M， Cordon-Cardo C， Gerald WL， et al. Desmoid fibromatosis is a clonal process[J]. Hum Pathol， 1996， 27(9)：939-943.
39. Jovanovic L， Delahunt B， Mciver B， et al. Thyroid gland clonality revisited：the embryonal patch size of the normal human thyroid gland is very large， suggesting X-chromosome inactivation tumor clonality studies of thyroid tumors have to be interpreted with caution[J]. J Clin Endocrinol Metab， 2003， 88(7)：3284-3291.
40. Riesco-Eizaguirre G， Santisteban P. Molecular biology of thyroid cancer initiation[J]. Clin Transl Oncol， 2007， 9(11)：686-693.
41. Kondo T， Ezzat S， Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia[J]. Nat Rev Cancer， 2006， 6(4)：292-306.
42. Xing M. BRAF mutation in thyroid cancer[J]. Endocr Relat Cancer， 2005， 12(2)：245-262.
43. Lee X， Gao M， Ji Y， et al. Analysis of differential BRAFV600E mutational status in high aggressive papillary thyroid microcarcinoma[J]. Ann Surg Oncol， 2009， 16(2)：240-245.
44. Park SY， Park YJ， Lee YJ， et al. Analysis of differential BRAFV600E mutational status in multifocal papillary thyroid carcinoma：evidence of independent clonal origin in distinct tumor foci[J]. Cancer， 2006， 107(8)：1831-1838.
45. Giannini R， Ugolini C， Lupi C， et al. The heterogeneous distribution of BRAF mutation supports the independent clonal origin of distinct tumor foci in multifocal papillary thyroid carcinoma[J]. J Clin Endocrinol Metab， 2007， 92(9)：3511-3516.
46. Jovanovic L， Delahunt B， Mciver B， et al. Most multifocal papillary thyroid carcinomas acquire genetic and morphotype diversity through subclonal evolution following the intra-glandular spread of the initial neoplastic clone[J]. J Pathol， 2008， 215(2)：145-154.
47. Segev DL， Umbricht C， Zeiger MA. Molecular pathogenesis of thyroid cancer[J]. Surg Oncol， 2003， 12(2）：69-90.
48. Cheung CC， Carydis B， Ezzat S， et al. Analysis of ret/PTC gene rearrangements refines the fine needle aspiration diagnosis of thyroid cancer[J]. J Clin Endocrinol Metab， 2001， 86(5)：2187-2190.
49. Unger K，Zitzelsberger H， Salvatore G， et al. Heterogeneity in the distribution of RET/PTC rearrangements within individual post-chernobyl papillary thyroid carcinomas[J]. J Clin Endocrinol Metab， 2004， 89(9)：4272-4279.
50. Santoro M， Melillo RM， Fusco A. RET/PTC activation in papillary thyroid carcinoma：European Journal of Endocrinology Prize Lecture[J]. Eur J Endocrinol， 2006， 155(5)：645-653.
51. Fusco A， Chiappetta G， Hui P， et al. Assessment of RET/PTC oncogene activation and clonality in thyroid nodules with incomplete morphological evidence of papillary carcinoma：a search for the early precursors of papillary cancer[J]. Am J Pathol， 2002， 160(6)：2157-2167.
52. Garcia-Rostan G， Zhao H， Camp RL， et al. ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer[J]. J Clin Oncol. 2003， 21(17)：3226-3235.
53. Nikiforov YE， Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer [J]. Nat Rev Endocrinol， 2011，7(10)：569-580．.
54. Donghi R， Longoni A， Pilotti S， et al. Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland[J]. J Clin Invest， 1993， 91(4)：1753-1760.
55. Ito T， Seyama T， Mizuno T， et al. Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland[J]. Cancer Res， 1992，52(5)：1369-1371.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Analysis of Clonal Origin of Thyroid Nodules

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