help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Segev, D. L.
Right arrow Articles by Zeiger, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Segev, D. L.
Right arrow Articles by Zeiger, M. A.
The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 6 2036-2042
Copyright © 1998 by The Endocrine Society

Original Studies

Polymerase Chain Reaction-Based Microsatellite Polymorphism Analysis of Follicular and Hürthle Cell Neoplasms of the Thyroid1

Dorry L. Segev, Motoyasu Saji, Grace S. Phillips, William H. Westra, Yumi Takiyama, Steven Piantadosi, Robert C. Smallridge2, Ronald H. Nishiyama, Robert Udelsman and Martha A. Zeiger

Department of Surgery, Division of Endocrine and Oncologic Surgery (D.L.S., M.S., G.P., Y.T., R.U., M.A.Z.), Departments of Pathology (W.H.W.) and Biostatistics (S.P.), the Johns Hopkins Medical Institutions, Baltimore, Maryland 21287; and Department of Medicine, Walter Reed Army Medical Center (R.C.S.), Washington, D.C. 20307; and Department of Pathology, Maine Medical Center (R.H.N.), Portland, Maine 04102

Address all correspondence and requests for reprints to: Dr. Martha A. Zeiger, 600 N. Wolfe Street, Carnegie 681, Department of Surgery, Division of Endocrine and Oncologic Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-8611. E-mail: mzeiger{at}welchlink.welch.jhu.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Follicular and Hürthle cell carcinomas of the thyroid cannot be differentiated from adenomas by either preoperative fine needle aspiration or intraoperative frozen section examination, and yet there exist potentially significant differences in the recommended surgical management. We examined, by PCR-based microsatellite polymorphism analysis, DNA obtained from 83 thyroid neoplasms [22 follicular adenomas, 29 follicular carcinomas, 20 Hürthle cell adenomas (HA), and 12 Hürthle cell carcinomas (HC)] to determine whether a pattern of allelic alteration exists that could help distinguish benign from malignant lesions. Alterations were found in only 7.5% of informative PCR reactions from follicular neoplasms, whereas they were found in 23.3% of reactions from Hürthle cell neoplasms. Although there were no significant differences between follicular adenoma and follicular carcinoma, HC demonstrated a significantly greater percentage of allelic alteration than HA on chromosomal arms 1q (P < 0.001) and 2p (P < 0.05) by Fisher’s exact test. The documentation of an alteration on either 1q or 2p was 100% sensitive and 65% specific in the detection of HC (P < 0.0005, by McNemar’s test).

In conclusion, PCR-based microsatellite polymorphism analysis may be a useful technique in distinguishing HC from HA. Potentially, the application of this technique to aspirated material may allow this distinction preoperatively and thus facilitate more optimal surgical management. Consistent regions of allelic alteration may also indicate the locations of critical genes, such as tumor suppressor genes or oncogenes, that are important in the progression from adenoma to carcinoma. Finally, this study demonstrates that Hürthle cell neoplasms, now considered variants of follicular neoplasms, differ significantly from follicular neoplasms on a molecular level.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
APPROXIMATELY half the population in the United States will develop a thyroid nodule by age 65 yr (1). Fine needle aspiration (FNA) cytology is the most accurate diagnostic test in the evaluation of these nodules (2, 3). However, FNA cannot distinguish benign from malignant follicular or Hürthle cell neoplasms (4, 5, 6, 7). Furthermore, intraoperative frozen section evaluation rarely yields additional useful information for the differential diagnosis of these neoplasms (8). The diagnosis of carcinoma requires the histological documentation on permanent section of tumor invasion, either into blood vessels or beyond the tumor capsule. In many cases, tumor invasion is a focal finding and apparent only upon careful analysis of multiple histological sections (9). Complicating this clinical dilemma, optimal surgical management of adenomas vs. carcinomas differs significantly; adenomas can be treated with lobectomy, whereas patients with carcinoma may benefit from total thyroidectomy (1, 10). As a definitive diagnosis can rarely be made either pre- or intraoperatively, patients with adenomas may undergo surgery that is more extensive than necessary, and conversely, patients with carcinomas may receive less than adequate surgery.

Recent studies have demonstrated that thyroid carcinomas may result from a series of defined genetic alterations (11). In terms of the distinction between follicular or Hürthle cell adenomas from carcinomas, others have examined these tumors by cytogenetic studies, loss of heterozygosity studies with restriction fragment length polymorphisms (12, 13, 14), as well as examination for mutations or overexpression of tumor suppressor genes and oncogenes, respectively (15, 16). We have previously demonstrated that measurement of telomerase activity can distinguish follicular carcinoma (FC) from follicular adenoma (FA) with 100% sensitivity and 76% specificity (17). Despite these studies, however, there is no other genetic abnormality that can reliably distinguish benign from malignant follicular or Hürthle cell neoplasms.

PCR-based microsatellite analysis is a more sensitive method than restriction fragment length polymorphism analysis for detecting chromosomal abnormalities (18, 19). In fact, allelotype analysis is now available for most tumor types and has been used in the evaluation of head and neck (20), renal (21), and colorectal (22) carcinomas. Zedenius et al. recently examined allelotypes of both follicular and Hürthle cell neoplasms by this method and demonstrated that 10q may be involved in follicular thyroid tumor progression and that the majority of Hürthle cell adenomas (HA) showed abnormalities on 3q or 18q (23, 24). Aberrations on chromosomal arms 3p and 11q have also been implicated by others in the progression of follicular neoplasms (12, 13, 25). We therefore examined allelotypes in 83 thyroid neoplasms [22 FA, 29 FC, 20 HA, and 12 Hürthle cell carcinomas (HC)] in an attempt to elucidate a genetic model of tumor progression and to identify a pattern of allelic alteration that might reliably distinguish benign from malignant neoplasms. We found that there was no difference in allelotyping between FA and FC, but that two chromosomal arms, 1q and 2p, had a significantly greater percentage of alterations in HC than in HA.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Thyroid tissue and DNA extraction

Paraffin-embedded or fresh-frozen follicular and Hürthle cell neoplasms and corresponding normal thyroid tissue and/or blood lymphocytes were collected from patients at the Johns Hopkins Medical Institutions, Walter Reed Army Medical Center, and Maine Medical Center. All tumors were primary thyroid tumors. Six to 10 adjacent 5-µm sections were cut from blocks and mounted on glass slides. All original slides stained with hematoxylin and eosin were reviewed to confirm the diagnosis by a single pathologist (W.H.W.). DNA from paraffin-embedded tissue or blood cells was extracted as previously described (26). DNA was extracted from frozen sections after microdissection and treatment with proteinase K followed by phenol-chloroform extraction, as described previously (26). Patients were studied under protocol M1011 approved by the Johns Hopkins Joint Committee on Clinical Investigation.

PCR-based microsatellite analysis

PCR reactions were performed as previously described (27, 28). Microsatellite primers were obtained from Research Genetics (Huntsville, AL), and their chromosomal locations were confirmed by marker maps obtained from the Cooperative Human Linkage Center worldwide web site.3 One primer from each pair was end labeled with T4 kinase (New England Biolabs, Beverly, MA) and {gamma}[32P]ATP (DuPont-New England Nuclear, Boston, MA). PCR reactions were carried out in a total volume of 10 µL containing 5–20 ng genomic DNA, 4 ng labeled primer, and 20 ng unlabeled primer in 35 cycles consisting of denaturing at 94 C for 60 s, annealing at 55–60 C for 60 s, and extension at 72 C for 120 s. After PCR, 5 µL of the reaction plus 5 µL 80% formamide were separated on a 40% formamide and 8.3 mol/L urea-6% polyacrylamide gel. Gels were dried, and autoradiography was performed with Kodak X-Omat (Eastman Kodak, Rochester, NY) for 4–48 h at room temperature or -70 C.

Definition of allelic alterations

For informative cases, alterations included allelic loss or gain (20, 23, 27) (Fig. 1Go). Loss was determined in heterozygous samples by comparing the intensity of the alleles in tumor DNA to that in corresponding normal DNA using densitometry (Molecular Dynamics, Sunnyvale, CA). If the ratio of the two alleles in normal DNA was twice that of the alleles in tumor DNA, it was considered an allelic loss. Gain of an allele was considered to exist if additional bands were noted. Constitutional homozygosity was regarded as noninformative.



View larger version (23K):
[in this window]
[in a new window]
  		Figure 1. Microsatellite analysis of representative cases. DNA from primary tumor (T) and corresponding normal thyroid or blood cells (N) were isolated and amplified by PCR. Microsatellite markers are designated below each figure: a, HC 9 shows retention of both alleles, and HA 24 and HC 25 show loss of lower allele in T at D1S1665 (1p); b, FA 5 shows retention of both alleles, and HC 9 shows loss of upper allele in T at D2S1326 (2q); and 3) FC 66 shows retention of both alleles, FC 67 shows gain of upper allele, and FC 68 shows loss of lower allele at D3S3038 (3p).

 
Statistical analysis

A tumor was considered positive for allelic alteration on a chromosomal arm if one or more markers demonstrated an alteration. For each marker and each chromosomal arm, the difference between the percent alteration for carcinoma and adenoma, defined as the number demonstrating alterations/number of informative cases, was tested for statistical significance using Fisher’s exact test with P < 0.05. Patterns of alteration on several chromosomal arms were examined by McNemar’s test for correlated proportions (29).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 83 follicular and Hürthle cell neoplasms of the thyroid (Table 1Go) were examined for allelic alteration by PCR-based microsatellite polymorphism analysis of most chromosomal arms using 65 microsatellite markers (Tables 2Go and 3Go). Among all informative PCR reactions from follicular neoplasms, 7.5% reactions showed alterations (5.8% in FA and 9.1% in FC). In contrast, 20.3% and 27.1% of informative reactions from HA and HC, respectively, displayed alterations (Table 1Go). There was no correlation between the percentage of allelic alteration and either tumor size or patient age for any group (Table 1Go).


View this table:
[in this window]
[in a new window]
  		Table 1. Follicular and Hürthle cell neoplasms, number, patient age, tumor size, and percentage of markers with alteration

 

View this table:
[in this window]
[in a new window]
  		Table 2. Summary of microsatellite analysis of follicular neoplasms

 

View this table:
[in this window]
[in a new window]
  		Table 3. Summary of microsatellite analysis of Hürthle cell neoplasms

 
There were no statistically significant differences in allelic alteration seen in FA vs. FC at any of the individual markers tested or on any chromosomal arm (Table 2Go and Fig. 2Go). Although there were also no statistically significant differences between HA and HC at any one marker (Table 3Go and Fig. 2Go), HC did demonstrate statistically significant differences compared to HA on chromosomal arms 1q (92% vs. 30%, P < 0.001) and 2p (50% vs. 12%, P < 0.05) by Fisher’s exact test (Table 3Go). In all cases the allelic patterns seen in normal thyroid corresponded to those seen in blood lymphocytes (data not shown).



View larger version (44K):
[in this window]
[in a new window]
  		Figure 2. Allelic alteration in follicular and Hürthle cell adenomas and carcinomas of the thyroid calculated as number of tumors with allelic alteration at one or more markers on the chromosomal arm/number of informative cases. * and **, Statistically significant differences per chromosomal arm by Fisher’s exact test (P < 0.05 and P < 0.001, respectively).

 
Combinations of alterations seen on several markers were examined by McNemar’s test for correlated proportions to determine whether there was a pattern that would reliably distinguish HA from HC. The combination of markers on chromosomal arm 1q (D1S534, D1S518, and D1S549) and that on 2p (D2S1780 and D2S1788) were statistically significantly different (Table 4Go). For instance, the demonstration of alteration on either 1q or 2p was 100% sensitive and 65% specific (P < 0.0005) in the detection of HC, with positive and negative predictive values of 63% and 100%, respectively.


View this table:
[in this window]
[in a new window]
  		Table 4. Specificity, sensitivity, and positive and negative predictive value in the detection of HC

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The exact molecular abnormalities responsible for the progression of normal thyroid tissue to thyroid neoplasia are poorly understood. Most thyroid neoplasms are clonal, arising from a single precursor cell that has acquired one or more mutations, thereby contributing to its uncontrolled growth (30). Although others have reported abnormalities on 3p and 11q in follicular neoplasms, 3q and 18q in Hürthle cell adenomas, and 10q in both FA and HA (14, 23, 24), our data demonstrated infrequent alterations on these chromosomal arms. This discrepancy may result from the fact that different markers were examined.

Because both follicular and Hürthle cell neoplasms demonstrate similar architectures on permanent histological section, Hürthle cell neoplasms are considered variants of follicular neoplasms (4, 7, 31). However, clinically, patients with HC have a worse prognosis than patients with FC (7, 31, 32, 33). Our results support this clinical difference insofar as we found that Hürthle cell neoplasms have a significantly higher frequency of allelic alteration than follicular neoplasms. Our data also support the idea that Hürthle cell neoplasms differ from follicular neoplasms on a molecular level and may explain their more aggressive behavior.

In this study, although we did not demonstrate a difference in allelic alterations between FC and FA, we did show that alterations on 1q and 2p were significantly more frequent in HC than HA. Various oncogenes and tumor suppressor genes have been described on these chromosomal arms (34, 35, 36, 37, 38, 39, 40, 41), each of which might be involved in the progression from benign to malignant Hürthle cell tumors. Whether the progression from HA to HC involves one or more of these genes or a novel gene might be better understood after more extensive microsatellite mapping studies of the neoplasms on 1q and 2p.

Relevant to the clinical dilemma of preoperative differentiation of Hürthle cell neoplasms, the pattern of chromosomal alteration on either 1q or 2p can distinguish HC from HA with 100% sensitivity and 65% specificity. Although our data are derived from frozen and paraffin-embedded neoplasms, preliminary work suggests that DNA extracted from corresponding FNA samples correlates with chromosomal alterations demonstrated in the tumors (26). Furthermore, allelic patterns were identical in normal thyroid and blood lymphocytes (data not shown), supporting the plausibility of using PCR-based microsatellite analysis of FNA samples and concomitant blood lymphocytes in the preoperative evaluation of Hürthle cell neoplasms of the thyroid.

In conclusion, the pattern of chromosomal alteration documented in this study may be important in further elucidating the genetic mechanisms responsible for thyroid carcinogenesis. The ability to distinguish HA from HC preoperatively also has enormous clinical and economic implications and theoretically may allow for more optimal surgical management of the patient harboring a Hürthle cell neoplasm.


   Acknowledgments
 
We thank Drs. David Sidransky, Joseph Califano, and Michael Johns, Jr. (Department of Otolaryngology, Johns Hopkins University, Baltimore, MD), and Michael Deavers, Maj., M.C., U.S.A. (Department of Surgical Pathology, Walter Reed Army Medical Center, Washington DC) for their generous assistance during this study.


   Footnotes
 
1 This work was supported by the Interthyr Research Foundation (to M.S.), the Johns Hopkins Oncology Center, and a NIH OPD-GCRC CAP award (to M.A.Z.). Back

2 Current address: Division of Endocrinology, Mayo Clinic Jacksonville, Jacksonville, Florida 32224. Back

3 World-Wide-Web site for Cooperative Human Linkage Center is www.chlc.org. The map used in this report was Sex-Averaged Recombination Minimization Maps of the Genome, Version 4.0, and Version 8.0 Likely Locations of Current CHLC Markers in Version 2.0 skeletal Maps. Back

Received September 15, 1997.

Revised January 12, 1998.

Accepted March 3, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Mazzaferri EL. 1993 Management of a solitary thyroid nodule. N Engl J Med. 328:553–559.[Free Full Text]
  2. Gharib H, Goellner JR. 1993 Fine-needle aspiration biopsy of the thyroid: an appraisal. Ann Intern Med. 118:282–289.[Abstract/Free Full Text]
  3. Hamburger JI, Kaplan NM. 1996 Evaluation of thyroid nodules by needle biopsy. In: Bravermann LE, Utiger RD, eds. The thyroid, 7th ed. Philadelphia: Lippincott-Raven; 447–460.
  4. Kini SR, Miller JM, Hamburger JI. 1981 Cytopathology of Hürthle cell lesions of the thyroid gland by fine needle aspiration. Acta Cytol. 25:647–652.[Medline]
  5. Carcangiu ML, Bianchi S, Savino D, Voynick IM, Rosai J. 1991 Follicular Hürthle cell tumors of the thyroid gland. Cancer. 68:1944–1953.[CrossRef][Medline]
  6. Gharib H. 1994 Fine-needle aspiration biopsy of thyroid nodules: advantages, limitations, and effect [Review]. Mayo Clin Proc. 69:44–49.[Medline]
  7. McLeod MK, Thompson NW. 1990 Hürthle cell neoplasms of the thyroid [Review]. Otolaryngol Clin North Am. 23:441–452.[Medline]
  8. Chen H, Nicol TL, Udelsman R. 1995 Follicular lesions of the thyroid: does frozen section evaluation alter operative management? Ann Surg. 222:101–106.[Medline]
  9. LiVolsi VA. 1996 Pathology. In: Bravermann LE, Utiger RD, eds. The thyroid, 7th ed. Phildelphia: Lippincott-Raven; 497–520.
  10. Singer PA, Cooper DS, Daniels GH, et al. 1996 Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association. Arch Intern Med. 156:2165–2172.[Abstract]
  11. Fagin JA. 1994 Molecular genetics of human thyroid neoplasms. Annu Rev Med. 45:45–52.[CrossRef][Medline]
  12. Matsuo K, Tang SH, Fagin JA. 1991 Allelotype of human thyroid tumors: loss of chromosome 11q13 sequences in follicular neoplasms. Mol Endocrinol. 5:1873–1879.[Abstract]
  13. Herrmann MA, Hay ID, Bartelt Jr DH, et al. 1991 Cytogenetic and molecular genetic studies of follicular and papillary thyroid cancers. J Clin Invest. 88:1596–1604.
  14. Tallini G, Ladanyi M, Rosai J, Jhanwar SC. 1994 Analysis of nuclear and mitochondrial DNA alteration in thyroid and renal oncocytic tumors. Cytogenet Cell Genet. 66:253–259.[Medline]
  15. Wynford-Thomas D. 1993 Molecular basis of epithelial tumorigenesis: the thyroid model [Review]. Crit Rev Oncog. 4:1–23.[Medline]
  16. Duh QY, Grossman RF. 1995 Thyroid growth factors, signal transduction pathways, and oncogenes [Review]. Surg Clin North Am. 75:421–437.[Medline]
  17. Umbricht CB, Saji M, Westra WH, Udelsman R, Zeiger MA, Sukumar S. 1997 Telomerase activity: a marker to distinguish follicular thyroid adenoma from carcinoma. Cancer Res. 57:2144–2147.[Abstract/Free Full Text]
  18. Bruford MW, Wayne RK. 1993 Microsatellites and their application to population genetic studies. Curr Opin Gene Dev. 3:939–943.[CrossRef][Medline]
  19. Naber SP. 1994 Molecular pathology–detection of neoplasia [see comments]. N Engl J Med. 331:1508–1510.[Free Full Text]
  20. Van der Riet P, Nawroz H, Hurban RH, et al. 1994 Frequent loss of chromosome 9p21–22 early in head and neck cancer progression. Cancer Res. 54:1156–1158.[Abstract/Free Full Text]
  21. Polascik TJ, Cairns P, Epstein JI, et al. 1996 Distal nephron renal tumors: microsatellite allelotype. Cancer Res. 56:1892–1895.[Abstract/Free Full Text]
  22. Thibodeau SN, Bren G, Schaid D. 1993 Microsatellite instability in cancer of the proximal colon [see comments]. Science. 260:816–819.[Abstract/Free Full Text]
  23. Zedenius J, Wallin G, Svensson A, et al. 1995 Allelotyping of follicular thyroid tumors. Hum Genet. 96:27–32.[CrossRef][Medline]
  24. Zedenius J, Wallin G, Svensson A, et al. 1996 Deletions of the long arm of chromosome 10 in progression of follicular thyroid tumors. Hum Genet. 97:299–303.[CrossRef][Medline]
  25. Fagin JA, Matsuo K, Karmakar A, Chen DL, Tang S, Koeffler HP. 1993 High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest. 91:179–184.
  26. Takiyama Y, Saji M, Clark DP, et al. 1997 PCR-based microsatellite analysis of fine needle aspirations (FNA) from Hürthle cell neoplasms. Thyroid. 7:853–857.[Medline]
  27. Mao L, Schoenberg MP, Scicchitano M, et al. 1996 Molecular detection of primary bladder cancer by microsatellite analysis. Science. 271:659–662.[Abstract]
  28. Califano J, Johns M, Westra WH, et al. 1996 An allelotype of papillary thyroid cancer. Int J Cancer. 69:442–444.[CrossRef][Medline]
  29. McNemar Q. 1947 Note on the sampling error of the difference between correlated proportions or percentages. Psychometrika. 12:153–157.[CrossRef]
  30. Namba H, Matsuo K, Fagin JA. 1990 Clonal composition of benign and malignant human thyroid tumors. J Clin Invest. 86:120–125.
  31. Tallini G, Carcangiu ML, Rosai J. 1992 Oncocytic neoplasms of the thyroid gland [Review]. Acta Pathol Jpn. 42:305–315.[Medline]
  32. Gosain AK, Clark OH. 1984 Hürthle cell neoplasms. Malignant potential. Arch Surg. 119:515–519.[Abstract]
  33. Grant CS. 1995 Operative and postoperative management of the patient with follicular and Hürthle cell carcinoma. Do they differ? [Review]. Surg Clin North Am. 75:395–403.[Medline]
  34. Pathak S, Goodacre A. 1986 Specific chromosome anomalies and predisposition to human breast, renal cell, and colorectal carcinoma. Cancer Genet Cytogenet. 19:29–36.[CrossRef][Medline]
  35. Chen LC, Neubauer A, Kurisu W, et al. 1991 Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer. Proc Natl Acad Sci USA. 88:3847–3851.[Abstract/Free Full Text]
  36. Rousseau-Merck MF, Zahraoui A, Touchot N, Tavitian A, Berger R. 1991 Chromosome assignment of four RAS-related RAB genes. Hum Genet. 86:350–354.[Medline]
  37. Peltomäki P, Aaltonen LA, Sistonen P, et al. 1993 Genetic mapping of a locus predisposing to human colorectal cancer. Science. 260:810–812.[Abstract/Free Full Text]
  38. Orth K, Hung J, Gazdar A, Bowcock A, Mathis JM, Sambrook J. 1994 Genetic instability in human ovarian cancer cell lines. Proc Natl Acad Sci USA. 91:9495–9499.[Abstract/Free Full Text]
  39. Weier HU, Rhein AP, Shadravan F, Collins C, Polikoff D. 1995 Rapid physical mapping of the human trk protooncogene (NTRK1) to human chromosome 1q21–q22 by P1 clone selection, fluorescence in situ hybridization (FISH), and computer-assisted microscopy. Genomics. 26:390–393.[CrossRef][Medline]
  40. Butti MG, Bongarzone I, Ferraresi G, Mondellini P, Borrello MG, Pierotti MA. 1995 A sequence analysis of the genomic regions involved in the rearrangements between TPM3 and NTRK1 genes producing TRK oncogenes in papillary thyroid carcinomas. Genomics. 28:15–24.[CrossRef][Medline]
  41. Wedemeyer N, Lengeling A, Ronsiek M, et al. 1996 YAC contigs of the Rab1 and wobbler (wr) spinal muscular atrophy gene region on proximal mouse chromosome 11 and of the homologous region on human chromosome 2p. Genomics. 32:447–454.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 J. Med. Genet.Home page
J D McKay, D Thompson, F Lesueur, K Stankov, A Pastore, C Watfah, S Strolz, G Riccabona, R Moncayo, G Romeo, et al.
Evidence for interaction between the TCO and NMTC1 loci in familial non-medullary thyroid cancer
J. Med. Genet., June 1, 2004; 41(6): 407 - 412.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. N. Nikiforova, R. A. Lynch, P. W. Biddinger, E. K. Alexander, G. W. Dorn II, G. Tallini, T. G. Kroll, and Y. E. Nikiforov
RAS Point Mutations and PAX8-PPAR{gamma} Rearrangement in Thyroid Tumors: Evidence for Distinct Molecular Pathways in Thyroid Follicular Carcinoma
J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2318 - 2326.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
C. A. French, E. K. Alexander, E. S. Cibas, V. Nose, J. Laguette, W. Faquin, J. Garber, F. Moore Jr, J. A. Fletcher, P. R. Larsen, et al.
Genetic and Biological Subgroups of Low-Stage Follicular Thyroid Cancer
Am. J. Pathol., April 1, 2003; 162(4): 1053 - 1060.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
V. B. Wreesmann, R. A. Ghossein, S. G. Patel, C. P. Harris, E. A. Schnaser, A. R. Shaha, R. M. Tuttle, J. P. Shah, P. H. Rao, and B. Singh
Genome-Wide Appraisal of Thyroid Cancer Progression
Am. J. Pathol., November 1, 2002; 161(5): 1549 - 1556.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
K. Farrand, B. Delahunt, X.-l. Wang, B. McIver, I. D. Hay, J. R. Goellner, N. L. Eberhardt, and S. K. G. Grebe
High Resolution Loss of Heterozygosity Mapping of 17p13 in Thyroid Cancer: Hurthle Cell Carcinomas Exhibit a Small 411-Kilobase Common Region of Allelic Imbalance, Probably Containing a Novel Tumor Suppressor Gene
J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4715 - 4721.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
Y. Kitamura, K. Shimizu, K. Ito, S. Tanaka, and M. Emi
Allelotyping of Follicular Thyroid Carcinoma: Frequent Allelic Losses in Chromosome Arms 7q, 11p, and 22q
J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4268 - 4272.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
C. A STRATAKIS, S. E TAYMANS, D. SCHTEINGART, and B. R HADDAD
Segmental uniparental isodisomy (UPD) for 2p16 without clinical symptoms: implications for UPD and other genetic studies of chromosome 2
J. Med. Genet., February 1, 2001; 38(2): 106 - 109.
[Full Text]

Home page
 Clin. Cancer Res.Home page
Y. Kitamura, K. Shimizu, S. Tanaka, K. Ito, and M. Emi
Association of Allelic Loss on 1q, 4p, 7q, 9p, 9q, and 16q with Postoperative Death in Papillary Thyroid Carcinoma
Clin. Cancer Res., May 1, 2000; 6(5): 1819 - 1825.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
Loss of Heterozygosity of the Long Arm of Chromosome 7 in Follicular and Anaplastic Thyroid Cancer, but Not in Papillary Thyroid Cancer
J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3235 - 3240.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Segev, D. L.
Right arrow Articles by Zeiger, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Segev, D. L.
Right arrow Articles by Zeiger, M. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals