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(American Journal of Pathology. 2002;160:1941-1944.)
© 2002 American Society for Investigative Pathology

Commentaries

Molecular Rearrangements and Morphology in Thyroid Cancer

Todd G. Kroll

From the Department of Pathology and Laboratory Medicine, the Department of Hematology and Oncology, the Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

Tumor development within the human thyroid gland provides an attractive experimental model with which to consider the pathogenesis of carcinoma, the most common and clinically significant cancer. Thyroid tumors are readily accessible to morphological and molecular study because their primary treatment is surgical. Investigations of thyroid cancer have expanded our knowledge of carcinoma biology. Thyroid carcinoma is the only adult epithelial malignancy in which specific chromosomal rearrangements have been identified.1-3 RET and PPAR{gamma} rearrangements in thyroid carcinoma create fusion proteins that are hypothesized to play fundamental roles in thyroid oncogenesis.3,4 The fusion protein pathways are prime targets for new strategies directed at improving thyroid cancer diagnosis and treatment.5-7

The RET proto-oncogene is interesting because it is mutated by different mechanisms in different (endocrine and neuroendocrine) thyroid carcinomas. RET rearrangement was discovered in papillary thyroid carcinoma,2 and it is an important pathogenic event in this cancer.4,8 On the other hand, activating RET point mutations/insertions are pathogenic in medullary thyroid carcinoma,9,10 which can manifest in either sporadic or familial form such as the multiple endocrine neoplasia type 2 syndrome.11-13 The molecular mechanisms associated with RET mutations in cancer are incompletely understood.

Our current concepts of chromosomal rearrangements in cancer are based primarily on investigations of blood cell malignancies. Chromosomal rearrangements in leukemias are genetic hits with complex functional consequences. Fusion proteins encoded by both derivative chromosomes have activities that often contribute uniquely to the neoplastic process.14,15 The fusion proteins can also inhibit their wild-type counterparts in a dominant-negative manner.17-19 Chromosomal rearrangements are early events that seem to require additional collaborating mutations and cellular alterations for cancer induction.16,20,21 Future studies will determine the extent to which rearrangement mechanisms are similar in carcinomas and noncarcinomas and the degree to which RET and other gene fusions may be useful in the management of thyroid cancer.

A study reported by Fusco and colleagues22 in this issue of The American Journal of Pathology correlates RET rearrangements with specific morphological patterns in thyroid tumors. The motivations are laudable but the undertaking is difficult because thyroid and other epithelial tumors typically consist of neoplastic cells intermingled irregularly with normal (connective tissue and vascular) and reactive (stromal and immune) cells in a solid tu-mor mass. Robust methods to analyze specific cell subpopulations within fresh and fixed epithelial tumors are needed.23,24 A main reason that blood cell malignancies have been so amenable to new molecular genetic approaches is that >90% pure populations of well-defined, viable tumor cells can often be obtained.25-28

Immunohistochemistry was performed by Fusco and colleagues22 with an affinity-purified polyclonal antiserum to detect RET protein expression. Because RET is not synthesized in normal follicular epithelial cells, immunoreactivity is thought to correlate with overexpression of the rearranged RET gene. However, the possibilities of confounding wild-type RET protein within thyroid tumors29-31 and/or cross-reactivity of the antiserum with receptors bearing homologous tyrosine kinase domains need to be kept in mind. The immunohistochemistry was coupled with reverse transcriptase-polymerase chain reaction and laser capture microdissection of paraffin-embedded tumor tissues to assess RET rearrangement status. Degraded mRNA in paraffin-embedded tissue reduces sensitivity and in this study control housekeeping transcripts were detected in only 7 of 14 cases, a highly select sample of the original 46 cases. Such high-cycle nested polymerase chain reaction and hybridization protocols are prone to contamination and low specificity, although appropriate negative and positive controls were reported. A common source of contamination/false-positives is purified plasmids and/or cell lines harboring rearrangements that are used to test assay sensitivity or to perform functional studies. Low specificity is often suggested by artifactual bands and smearing seen with ethidium bromide staining. The androgen receptor clonality assay was also conducted on DNA obtained from manually dissected paraffin-embedded tissue, and it is somewhat surprising that all four follicular adenomas were polyclonal. Nearly all follicular adenomas in the literature are monoclonal.32-34 On the other hand, this may be a special mixed group of tumors. Two of the hyperplastic nodules were monoclonal and two were polyclonal, consistent with the clonality reported in the literature.35-37 Based on these considerations, this study must be interpreted conservatively and additional experiments with fresh tissue (fragments or frozen sections) and complimentary methods such as fluorescence in situ hybridization will be needed to corroborate RET rearrangement at the DNA level.

Putting aside potential technical caveats, the data of Fusco and colleagues22 show that RET rearrangement can occur within "morphologically benign" thyroid nodules. Two main tumor groups were seen. In the first group, three tumors exhibited RET rearrangement in focal areas of well-developed papillary carcinoma-like morphological change (type A), consistent with the idea that these are small papillary carcinomas arising within benign thyroid nodules. This contention would not be surprising to most pathologists who often observe small papillary carcinoma-like foci dispersed widely within thyroid tissue in both surgery and autopsy material. The distribution of these foci within the nodules seems inconsistent with the theoretical possibility that they preceded growth of the remaining tumor. In fact, all three tumors had foci with RET/PTC1 rearrangement, which is the most prevalent rearranged RET form in the small classic and occult/microcarcinoma38-40 papillary carcinoma subtypes. Two of these three nodules were polyclonal, as would also be expected if they contained co-existing tumors. Thus, tumor morphology and molecular genetics seem concordant in this group.

In the second group, two of six tumors with widespread but weak papillary carcinoma-like morphological change (type D) exhibited RET/PTC3 rearrangement, consistent with the idea that these are carcinomas with variable papillary nuclear morphology. In support of this possibility, one tumor was monoclonal, as would be expected for a papillary carcinoma. The other tumor could not be tested. Two other tumors with type D morphology were negative for RET rearrangement and the remaining two tumors were not tested. Thus, tumor morphology and molecular genetics seem discordant in this group.

Interestingly, other recent studies affirm a discordance between RET rearrangement status and papillary thyroid carcinoma-like morphology in thyroid tumors. For example, up to 50% of Hurthle cell thyroid tumors harbor RET rearrangements,41,42 despite the widely held view that they are more closely related to follicular tumors than to papillary carcinoma. In addition, papillary carcinomas containing RET/PTC3 rearrangement exhibit a spectrum of histologies (classic, solid, and tall cell) that have different biological tendencies.43-45 Thyroid tumors with mixed morphological and clinical features of papillary and follicular carcinoma have also been described.46 These findings suggest that there is an imprecision in our morphological categorization of thyroid tumors and that unknown cellular factors cooperate with RET rearrangement to determine papillary carcinoma morphology and biology. The overall findings of Fusco and colleagues22 suggest that we have much to learn regarding thyroid cancer pathogenesis and the degree to which thyroid tumor morphology correlates with underlying molecular genetic events.

The imprecise nature of papillary carcinoma morphology makes pathological diagnosis of thyroid tumors difficult. The issue is complicated by varied approaches of pathologists to follicular-patterned thyroid tumors.47-49 Even so, it is likely such imprecision has little clinical impact because nearly all low-stage thyroid cancers have excellent prognosis. Whereas it might be informative from a biological perspective to better define the biology of the tumors in this study, from a clinical perspective they will likely behave at worst like well-differentiated thyroid cancer, a readily curable disease. In fact, 80 to 90% of thyroid nodules now removed by surgery are benign, and we therefore may actually be overtreating many patients with thyroid nodules to exclude the possibility of cancer. The most rational long-term clinical goal is to increase our ability to differentially diagnose benign from malignant/precursor thyroid nodules before surgery so that appropriate, more individualized treatments can be rendered.

In summary, the results of Fusco and colleagues22 suggest that some thyroid nodules with a predominance of benign morphological features have RET rearrangement. Techniques such as fluorescence in situ hybridization will be needed to document the existence, frequency, and geographic distribution of RET rearrangements in these relatively rare tumors. The study highlights an imprecision in our morphological classification of papillary carcinoma-like tumors, making it more likely that molecular endocrine tumor markers will help us subdivide thyroid and other endocrine tumors into more distinct biological subgroups. Regardless of whether morphological or molecular markers are considered, their clinical utility is dependent strictly on tumor biology and clinical context. It is therefore critical that well-organized clinical databases containing comprehensive patient information and clinical follow-up data be constructed to rigorously define clinicopathological correlates of putative biomarkers identified with the new molecular genetic techniques.50 Thyroid cancer is no exception in this respect.

Footnotes

Address reprint requests to Todd G. Kroll, M.D., Ph.D., Pathology and Laboratory Medicine Department, Emory University School of Medicine, 146 Whitehead Building, 615 Michael St., Atlanta, GA 30322. E-mail: tkroll{at}emory.edu

Accepted for publication April 4, 2002.

References

  1. Fusco A, Grieco M, Santoro M, Berlingieri MT, Pilotti S, Pierotti MA, Della Porta G, Vecchio G: A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 1987, 328:170-172[Medline]
  2. Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A, Vecchio G: Ptc is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990, 60:557-563[Medline]
  3. Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, Fletcher JA: Pax8-Ppargamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 2000, 289:1357-1360[Abstract/Free Full Text]
  4. Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G, Picone A, Portella G, Santelli G, Vecchio G, Fusco A: Development of thyroid papillary carcinomas secondary to tissue-specific expression of the Ret/Ptc1 oncogene in transgenic mice. Oncogene 1996, 12:1821-1826[Medline]
  5. Mauro MJ, O’Dwyer M, Heinrich MC, Druker BJ: Sti571: a paradigm of new agents for cancer therapeutics. J Clin Oncol 2002, 20:325-334[Abstract/Free Full Text]
  6. Druker BJ: Perspectives on the development of a molecularly targeted agent. Cancer Cell 2002, 1:31-36[Medline]
  7. Piazza F, Gurrieri C, Pandolfi PP: The theory of Apl. Oncogene 2001, 20:7216-7222[Medline]
  8. Jhiang SM, Sagartz JE, Tong Q, Parker-Thornburg J, Capen CC, Cho JY, Xing S, Ledent C: Targeted expression of the Ret/Ptc1 oncogene induces papillary thyroid carcinomas. Endocrinology 1996, 137:375-378[Abstract]
  9. Kawai K, Iwashita T, Murakami H, Hiraiwa N, Yoshiki A, Kusakabe M, Ono K, Iida K, Nakayama A, Takahashi M: Tissue-specific carcinogenesis in transgenic mice expressing the Ret proto-oncogene with a multiple endocrine neoplasia type 2a mutation. Cancer Res 2000, 60:5254-5260[Abstract/Free Full Text]
  10. Michiels FM, Chappuis S, Caillou B, Pasini A, Talbot M, Monier R, Lenoir GM, Feunteun J, Billaud M: Development of medullary thyroid carcinoma in transgenic mice expressing the Ret protooncogene altered by a multiple endocrine neoplasia type 2a mutation. Proc Natl Acad Sci USA 1997, 94:3330-3335[Abstract/Free Full Text]
  11. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA, Jr: Mutations in the Ret proto-oncogene are associated with Men 2a and Fmtc. Hum Mol Genet 1993, 2:851-856[Abstract/Free Full Text]
  12. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder B: Germ-line mutations of the Ret proto-oncogene in multiple endocrine neoplasia type 2a. Nature 1993, 363:458-460[Medline]
  13. Smith DP, Eng C, Ponder BA: Mutations of the Ret proto-oncogene in the multiple endocrine neoplasia type 2 syndromes and Hirschsprung disease. J Cell Sci Suppl 1994, 18:S43-S49
  14. He LZ, Bhaumik M, Tribioli C, Rego EM, Ivins S, Zelent A, Pandolfi PP: Two critical hits for promyelocytic leukemia. Mol Cell 2000, 6:1131-1141[Medline]
  15. Pollock JL, Westervelt P, Kurichety AK, Pelicci PG, Grisolano JL, Ley TJ: A Bcr-3 isoform of Raralpha-Pml potentiates the development of Pml-Raralpha-driven acute promyelocytic leukemia. Proc Natl Acad Sci USA 1999, 96:15103-15108[Abstract/Free Full Text]
  16. Huettner CS, Zhang P, Van Etten RA, Tenen DG: Reversibility of acute B-cell leukaemia induced by Bcr-Abl1. Nat Genet 2000, 24:57-60[Medline]
  17. Salomoni P, Pandolfi PP: The role of Pml in tumor suppression. Cell 2002, 108:165-170[Medline]
  18. Downing JR, Higuchi M, Lenny N, Yeoh AE: Alterations of the Aml1 transcription factor in human leukemia. Semin Cell Dev Biol 2000, 11:347-360[Medline]
  19. Melnick A, Carlile GW, McConnell MJ, Polinger A, Hiebert SW, Licht JD: Aml-1/Eto fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein. Blood 2000, 96:3939-3947[Abstract/Free Full Text]
  20. Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hetherington CJ, Burel SA, Lagasse E, Weissman IL, Akashi K, Zhang DE: Aml1-Eto expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci USA 2001, 98:10398-10403[Abstract/Free Full Text]
  21. Higuchi M, O’Brien D, Kumaravelu P, Lenny N, Yeoh E, Downing J: Expression of a conditional Aml-Eto oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 2002, 1:63-74[Medline]
  22. Fusco A, Chiappetta G, Hui P, Garcia-Rostan G, Golden L, Kinder BK, Dillon DA, Giuliano A, Cirafici A, Santoro M, Rosai J, Tallini G: 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. Am J Pathol 2002, 160:2157-2167[Abstract/Free Full Text]
  23. Maitra A, Wistuba II, Virmani AK, Sakaguchi M, Park I, Stucky A, Milchgrub S, Gibbons D, Minna JD, Gazdar AF: Enrichment of epithelial cells for molecular studies. Nat Med 1999, 5:459-463[Medline]
  24. Sugiyama Y, Sugiyama K, Hirai Y, Akiyama F, Hasumi K: Microdissection is essential for gene expression profiling of clinically resected cancer tissues. Am J Clin Pathol 2002, 117:109-116[Abstract/Free Full Text]
  25. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, Coller H, Loh ML, Downing JR, Caligiuri MA, Bloomfield CD, Lander ES: Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999, 286:531-537[Abstract/Free Full Text]
  26. Ferrando A, Neuberg D, Staunton J, Loh M, Huard C, Raimondi S, Behm F, Pui C, Downing J, Gilliland D, Lander E, Golub T, Look A: Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 2002, 1:75-87[Medline]
  27. Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD, Sallan SE, Lander ES, Golub TR, Korsmeyer SJ: Mll translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 2002, 30:41-47[Medline]
  28. Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X, Yang L, Pickeral OK, Rassenti LZ, Powell J, Botstein D, Byrd JC, Grever MR, Cheson BD, Chiorazzi N, Wilson WH, Kipps TJ, Brown PO, Staudt LM: Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001, 194:1639-1647[Abstract/Free Full Text]
  29. Bunone G, Uggeri M, Mondellini P, Pierotti MA, Bongarzone I: Ret receptor expression in thyroid follicular epithelial cell-derived tumors. Cancer Res 2000, 60:2845-2849[Abstract/Free Full Text]
  30. Fluge O, Haugen DR, Akslen LA, Marstad A, Santoro M, Fusco A, Varhaug JE, Lillehaug JR: Expression and alternative splicing of C-Ret RNA in papillary thyroid carcinomas. Oncogene 2001, 20:885-892[Medline]
  31. Kjellman P, Learoyd DL, Messina M, Weber G, Hoog A, Wallin G, Larsson C, Robinson BG, Zedenius J: Expression of the Ret proto-oncogene in papillary thyroid carcinoma and its correlation with clinical outcome. Br J Surg 2001, 88:557-563[Medline]
  32. Namba H, Matsuo K, Fagin JA: Clonal composition of benign and malignant human thyroid tumors. J Clin Invest 1990, 86:120-125
  33. Hicks DG, LiVolsi VA, Neidich JA, Puck JM, Kant JA: Clonal analysis of solitary follicular nodules in the thyroid. Am J Pathol 1990, 137:553-562[Abstract]
  34. Moniz S, Catarino AL, Marques AR, Cavaco B, Sobrinho L, Leite V: clonal origin of non-medullary thyroid tumours assessed by non-random X-chromosome inactivation. Eur J Endocrinol 2002, 146:27-33[Abstract]
  35. Kopp P, Kimura ET, Aeschimann S, Oestreicher M, Tobler A, Fey MF, Studer H: Polyclonal and monoclonal thyroid nodules coexist within human multinodular goiters. J Clin Endocrinol Metab 1994, 79:134-139[Abstract]
  36. Apel RL, Ezzat S, Bapat BV, Pan N, LiVolsi VA, Asa SL: Clonality of thyroid nodules in sporadic goiter. Diagn Mol Pathol 1995, 4:113-121[Medline]
  37. Chung DH, Kang GH, Kim WH, Ro JY: Clonal analysis of a solitary follicular nodule of the thyroid with the polymerase chain reaction method. Mod Pathol 1999, 12:265-271[Medline]
  38. Viglietto G, Chiappetta G, Martinez-Tello FJ, Fukunaga FH, Tallini G, Rigopoulou D, Visconti R, Mastro A, Santoro M, Fusco A: Ret/Ptc oncogene activation is an early event in thyroid carcinogenesis. Oncogene 1995, 11:1207-1210[Medline]
  39. Tallini G, Santoro M, Helie M, Carlomagno F, Salvatore G, Chiappetta G, Carcangiu ML, Fusco A: Ret/Ptc oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res 1998, 4:287-294[Abstract/Free Full Text]
  40. Sugg SL, Ezzat S, Rosen IB, Freeman JL, Asa SL: Distinct multiple Ret/Ptc gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab 1998, 83:4116-4122[Abstract/Free Full Text]
  41. Chiappetta G, Toti P, Cetta F, Giuliano A, Pentimalli F, Amendola I, Lazzi S, Monaco M, Mazzuchelli L, Tosi P, Santoro M, Fusco A: The Ret/Ptc oncogene is frequently activated in oncocytic thyroid tumors (Hurthle cell adenomas and carcinomas), but not in oncocytic hyperplastic lesions. J Clin Endocrinol Metab 2002, 87:364-369[Abstract/Free Full Text]
  42. Cheung CC, Ezzat S, Ramyar L, Freeman JL, Asa SL: Molecular basis of Hurthle cell papillary thyroid carcinoma. J Clin Endocrinol Metab 2000, 85:878-882[Abstract/Free Full Text]
  43. Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA: Distinct pattern of Ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 1997, 57:1690-1694[Abstract/Free Full Text]
  44. Thomas GA, Bunnell H, Cook HA, Williams ED, Nerovnya A, Cherstvoy ED, Tronko ND, Bogdanova TI, Chiappetta G, Viglietto G, Pentimalli F, Salvatore G, Fusco A, Santoro M, Vecchio G: High prevalence of Ret/Ptc rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between Ret/Ptc3 and the solid-follicular variant. J Clin Endocrinol Metab 1999, 84:4232-4238[Abstract/Free Full Text]
  45. Basolo F, Giannini R, Monaco C, Melillo RM, Carlomagno F, Pancrazi M, Salvatore G, Chiappetta G, Pacini F, Elisei R, Miccoli P, Pinchera A, Fusco A, Santoro M: Potent mitogenicity of the Ret/Ptc3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma. Am J Pathol 2002, 160:247-254[Abstract/Free Full Text]
  46. Baloch ZW, LiVolsi VA: Encapsulated follicular variant of papillary thyroid carcinoma with bone metastases. Mod Pathol 2000, 13:861-865[Medline]
  47. Renshaw AA, Gould EW: Why there is the tendency to "overdiagnose" the follicular variant of papillary thyroid carcinoma. Am J Clin Pathol 2002, 117:19-21[Free Full Text]
  48. Chan JK: Strict criteria should be applied in the diagnosis of encapsulated follicular variant of papillary thyroid carcinoma. Am J Clin Pathol 2002, 117:16-18[Free Full Text]
  49. Baloch ZW, Livolsi VA: Follicular-patterned lesions of the thyroid: the bane of the pathologist. Am J Clin Pathol 2002, 117:143-150[Abstract/Free Full Text]
  50. Becich MJ: The role of the pathologist as tissue refiner and data miner: the impact of functional genomics on the modern pathology laboratory and the critical roles of pathology informatics and bioinformatics. Mol Diagn 2000, 5:287-299[Medline]



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