Genome-wide profiling of papillary thyroid cancer identities MUC1 as an independent prognostic marker

Volkert B. Wreesmann, Elizabeth M. Sieczka, Nicholas D. Socci, Michael Hezel, Thomas J. Belbin, Geoffrey J. Childs, Snehal G. Patel, Kepal N. Patel, Giovanni Tallini, Michael B. Prystowsky, Ashok R. Shaha, Dennis Kraus, Jalin P. Shah, Pulivarthi H. Rao, Ronald Ghossein, Bhuvanesh Singh

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

Clinicopathological variables used at present for prognostication and treatment selection for papillary thyroid carcinomas (PTCs) do not uniformly predict tumor behavior, necessitating identification of novel prognostic markers. Complicating the assessment is the long natural history of PTC and our rudimentary knowledge of its genetic composition. In this study we took advantage of differences in clinical behavior of two distinct variants of PTC, the aggressive tall-cell variant (TCV) and indolent conventional PTC (cPTC), to identify molecular prognosticators of outcome using complementary genome wide analyses. Comparative genome hybridization (CGH) and cDNA microarray (17,840 genes) analyses were used to detect changes in DNA copy number and gene expression in pathological CPTC and TCV. The findings from CGH and cDNA microarray analyses were correlated and validated by real-time PCR and immunohistochemical analyses on a series of 100 cases of cPTC and TCV. Genes identified by this approach were evaluated as prognostic markers in cPTC by immunohistochemistry on tissue arrays. CGH identified significant differences in the presence (76 versus 27%; P = 0.001) and type of DNA copy number aberrations in TCV compared with cPTC. Recurrent gains of 1p34-36, 1q21, 6p21-22, 9q34, 11q13, 17q25, 19, and 22 and losses of 2q21-31, 4, 5p14-q21, 6q11-22, 8q11-22, 9q11-32, and 13q21, were unique to TCV. Hierarchical clustering of gene expression profiles revealed significant overlap between TCV and cPTC, but further analysis identified 82 dysregulated genes differentially expressed among the PTC variants. Of these, MUC1 was of particular interest because amplification of 1q by CGH correlated with MUC1 amplification by real-time PCR analysis and protein overexpression by immunohistochemistry in TCV (P = 0.005). Multivariate analysis revealed a significant association between MUC1 overexpression and treatment outcome, independent of histopathological categorization (P = 0.03). Analysis of a validation series containing a matched group of aggressive and indolent cPTCs confirmed the association between MUC1 overexpression and survival (relative risk, 2.3; 95% confidence interval, 1.1-5.5; P = 0.03). Our data suggest that MUC1 dysregulation is associated with aggressive behavior of PTC and may serve as a prognostic marker and potential therapeutic target in this disease.

Original languageEnglish (US)
Pages (from-to)3780-3789
Number of pages10
JournalCancer Research
Volume64
Issue number11
DOIs
StatePublished - Jun 1 2004

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Genome
Factor IX
Comparative Genomic Hybridization
Oligonucleotide Array Sequence Analysis
Real-Time Polymerase Chain Reaction
Immunohistochemistry
DNA Copy Number Variations
Genes
Microarray Analysis
Papillary Thyroid cancer
Natural History
Transcriptome
Cluster Analysis
Research Design
Multivariate Analysis
Confidence Intervals
Gene Expression
DNA
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wreesmann, V. B., Sieczka, E. M., Socci, N. D., Hezel, M., Belbin, T. J., Childs, G. J., ... Singh, B. (2004). Genome-wide profiling of papillary thyroid cancer identities MUC1 as an independent prognostic marker. Cancer Research, 64(11), 3780-3789. https://doi.org/10.1158/0008-5472.CAN-03-1460

Genome-wide profiling of papillary thyroid cancer identities MUC1 as an independent prognostic marker. / Wreesmann, Volkert B.; Sieczka, Elizabeth M.; Socci, Nicholas D.; Hezel, Michael; Belbin, Thomas J.; Childs, Geoffrey J.; Patel, Snehal G.; Patel, Kepal N.; Tallini, Giovanni; Prystowsky, Michael B.; Shaha, Ashok R.; Kraus, Dennis; Shah, Jalin P.; Rao, Pulivarthi H.; Ghossein, Ronald; Singh, Bhuvanesh.

In: Cancer Research, Vol. 64, No. 11, 01.06.2004, p. 3780-3789.

Research output: Contribution to journalArticle

Wreesmann, VB, Sieczka, EM, Socci, ND, Hezel, M, Belbin, TJ, Childs, GJ, Patel, SG, Patel, KN, Tallini, G, Prystowsky, MB, Shaha, AR, Kraus, D, Shah, JP, Rao, PH, Ghossein, R & Singh, B 2004, 'Genome-wide profiling of papillary thyroid cancer identities MUC1 as an independent prognostic marker', Cancer Research, vol. 64, no. 11, pp. 3780-3789. https://doi.org/10.1158/0008-5472.CAN-03-1460
Wreesmann, Volkert B. ; Sieczka, Elizabeth M. ; Socci, Nicholas D. ; Hezel, Michael ; Belbin, Thomas J. ; Childs, Geoffrey J. ; Patel, Snehal G. ; Patel, Kepal N. ; Tallini, Giovanni ; Prystowsky, Michael B. ; Shaha, Ashok R. ; Kraus, Dennis ; Shah, Jalin P. ; Rao, Pulivarthi H. ; Ghossein, Ronald ; Singh, Bhuvanesh. / Genome-wide profiling of papillary thyroid cancer identities MUC1 as an independent prognostic marker. In: Cancer Research. 2004 ; Vol. 64, No. 11. pp. 3780-3789.
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T1 - Genome-wide profiling of papillary thyroid cancer identities MUC1 as an independent prognostic marker

AU - Wreesmann, Volkert B.

AU - Sieczka, Elizabeth M.

AU - Socci, Nicholas D.

AU - Hezel, Michael

AU - Belbin, Thomas J.

AU - Childs, Geoffrey J.

AU - Patel, Snehal G.

AU - Patel, Kepal N.

AU - Tallini, Giovanni

AU - Prystowsky, Michael B.

AU - Shaha, Ashok R.

AU - Kraus, Dennis

AU - Shah, Jalin P.

AU - Rao, Pulivarthi H.

AU - Ghossein, Ronald

AU - Singh, Bhuvanesh

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N2 - Clinicopathological variables used at present for prognostication and treatment selection for papillary thyroid carcinomas (PTCs) do not uniformly predict tumor behavior, necessitating identification of novel prognostic markers. Complicating the assessment is the long natural history of PTC and our rudimentary knowledge of its genetic composition. In this study we took advantage of differences in clinical behavior of two distinct variants of PTC, the aggressive tall-cell variant (TCV) and indolent conventional PTC (cPTC), to identify molecular prognosticators of outcome using complementary genome wide analyses. Comparative genome hybridization (CGH) and cDNA microarray (17,840 genes) analyses were used to detect changes in DNA copy number and gene expression in pathological CPTC and TCV. The findings from CGH and cDNA microarray analyses were correlated and validated by real-time PCR and immunohistochemical analyses on a series of 100 cases of cPTC and TCV. Genes identified by this approach were evaluated as prognostic markers in cPTC by immunohistochemistry on tissue arrays. CGH identified significant differences in the presence (76 versus 27%; P = 0.001) and type of DNA copy number aberrations in TCV compared with cPTC. Recurrent gains of 1p34-36, 1q21, 6p21-22, 9q34, 11q13, 17q25, 19, and 22 and losses of 2q21-31, 4, 5p14-q21, 6q11-22, 8q11-22, 9q11-32, and 13q21, were unique to TCV. Hierarchical clustering of gene expression profiles revealed significant overlap between TCV and cPTC, but further analysis identified 82 dysregulated genes differentially expressed among the PTC variants. Of these, MUC1 was of particular interest because amplification of 1q by CGH correlated with MUC1 amplification by real-time PCR analysis and protein overexpression by immunohistochemistry in TCV (P = 0.005). Multivariate analysis revealed a significant association between MUC1 overexpression and treatment outcome, independent of histopathological categorization (P = 0.03). Analysis of a validation series containing a matched group of aggressive and indolent cPTCs confirmed the association between MUC1 overexpression and survival (relative risk, 2.3; 95% confidence interval, 1.1-5.5; P = 0.03). Our data suggest that MUC1 dysregulation is associated with aggressive behavior of PTC and may serve as a prognostic marker and potential therapeutic target in this disease.

AB - Clinicopathological variables used at present for prognostication and treatment selection for papillary thyroid carcinomas (PTCs) do not uniformly predict tumor behavior, necessitating identification of novel prognostic markers. Complicating the assessment is the long natural history of PTC and our rudimentary knowledge of its genetic composition. In this study we took advantage of differences in clinical behavior of two distinct variants of PTC, the aggressive tall-cell variant (TCV) and indolent conventional PTC (cPTC), to identify molecular prognosticators of outcome using complementary genome wide analyses. Comparative genome hybridization (CGH) and cDNA microarray (17,840 genes) analyses were used to detect changes in DNA copy number and gene expression in pathological CPTC and TCV. The findings from CGH and cDNA microarray analyses were correlated and validated by real-time PCR and immunohistochemical analyses on a series of 100 cases of cPTC and TCV. Genes identified by this approach were evaluated as prognostic markers in cPTC by immunohistochemistry on tissue arrays. CGH identified significant differences in the presence (76 versus 27%; P = 0.001) and type of DNA copy number aberrations in TCV compared with cPTC. Recurrent gains of 1p34-36, 1q21, 6p21-22, 9q34, 11q13, 17q25, 19, and 22 and losses of 2q21-31, 4, 5p14-q21, 6q11-22, 8q11-22, 9q11-32, and 13q21, were unique to TCV. Hierarchical clustering of gene expression profiles revealed significant overlap between TCV and cPTC, but further analysis identified 82 dysregulated genes differentially expressed among the PTC variants. Of these, MUC1 was of particular interest because amplification of 1q by CGH correlated with MUC1 amplification by real-time PCR analysis and protein overexpression by immunohistochemistry in TCV (P = 0.005). Multivariate analysis revealed a significant association between MUC1 overexpression and treatment outcome, independent of histopathological categorization (P = 0.03). Analysis of a validation series containing a matched group of aggressive and indolent cPTCs confirmed the association between MUC1 overexpression and survival (relative risk, 2.3; 95% confidence interval, 1.1-5.5; P = 0.03). Our data suggest that MUC1 dysregulation is associated with aggressive behavior of PTC and may serve as a prognostic marker and potential therapeutic target in this disease.

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