DNA copy number variations characterize benign and malignant thyroid tumors

Yan Liu, Leslie Cope, Wenyue Sun, Yongchun Wang, Nijaguna Prasad, Lauren Sangenario, Kristen Talbot, Helina Somervell, William Westra, Justin Bishop, Joseph Califano, Martha Zeiger, Christopher Umbricht

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Context: Fine-needle aspiration (FNA) is the best diagnostic tool for preoperative evaluation of thyroid nodules but is often inconclusive as a guide for surgical management. Objective: Our hypothesis was that thyroid tumor subtypes may show characteristic DNA copy number variation (CNV) patterns, which may further improve the preoperative classification. Design: Our study cohorts included benign follicular adenomas (FAs), classic papillary thyroid carcinomas (PTCs), and follicular variant PTCs (FVPTCs), the three subtypes most commonly associated with inconclusive preoperative cytopathology. Setting: Tissue and FNA samples were obtained at an academic tertiary referral center. Patients: Cases were identified that underwent partial or complete thyroidectomy for malignant or indeterminate thyroid lesions between 2000 and 2008 and had adequate snap-frozen tissue. Interventions: Pairs of tumor tissue and matching normal thyroid tissue-derived DNA were compared using 550K single-nucleotide polymorphism arrays. Main Outcome Measure: Statistically significant differences in CNV patterns between tumor subtypes were identified. Results: Segmental amplifications in chromosomes (Ch) 7 and 12 were more common in FAs than in PTCs or FVPTCs. Additionally, a subset of FAs and FVPTCs showed deletions in Ch22. Weidentified the 5 CNV-associated genes best at discriminating between FAs and PTCs/FVPTCs, which correctly classified 90% of cases. These 5 Ch12 genes were validated by quantitative genomic PCR and gene expression array analyses on the same patient cohort. The 5-gene signature was then successfully validated against an independent test cohort of benign and malignant tumor samples. Finally, we performed a feasibility study on matched FA-derived intraoperative FNA samples and were able to correctly identify FAs harboring the Ch12 amplification signature, whereas FAs without amplification showed a normal Ch12 signature. Conclusions: Thyroid tumor subtypes possess characteristic genomic profiles that may further our understanding of structural genetic changes in thyroid tumor subtypes and may lead to the development of new diagnostic biomarkers in FNA samples.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Volume98
Issue number3
DOIs
StatePublished - Mar 1 2013

Fingerprint

DNA Copy Number Variations
Adenoma
Tumors
Thyroid Gland
Needles
Factor IX
Fine Needle Biopsy
DNA
Tissue
Amplification
Neoplasms
Genes
Follicular Adenocarcinoma
Chromosomes, Human, Pair 12
Biomarkers
Chromosomes
Thyroid Nodule
Chromosomes, Human, Pair 7
Polymorphism
Gene expression

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

DNA copy number variations characterize benign and malignant thyroid tumors. / Liu, Yan; Cope, Leslie; Sun, Wenyue; Wang, Yongchun; Prasad, Nijaguna; Sangenario, Lauren; Talbot, Kristen; Somervell, Helina; Westra, William; Bishop, Justin; Califano, Joseph; Zeiger, Martha; Umbricht, Christopher.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 98, No. 3, 01.03.2013.

Research output: Contribution to journalArticle

Liu, Y, Cope, L, Sun, W, Wang, Y, Prasad, N, Sangenario, L, Talbot, K, Somervell, H, Westra, W, Bishop, J, Califano, J, Zeiger, M & Umbricht, C 2013, 'DNA copy number variations characterize benign and malignant thyroid tumors', Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 3. https://doi.org/10.1210/jc.2012-3113
Liu, Yan ; Cope, Leslie ; Sun, Wenyue ; Wang, Yongchun ; Prasad, Nijaguna ; Sangenario, Lauren ; Talbot, Kristen ; Somervell, Helina ; Westra, William ; Bishop, Justin ; Califano, Joseph ; Zeiger, Martha ; Umbricht, Christopher. / DNA copy number variations characterize benign and malignant thyroid tumors. In: Journal of Clinical Endocrinology and Metabolism. 2013 ; Vol. 98, No. 3.
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abstract = "Context: Fine-needle aspiration (FNA) is the best diagnostic tool for preoperative evaluation of thyroid nodules but is often inconclusive as a guide for surgical management. Objective: Our hypothesis was that thyroid tumor subtypes may show characteristic DNA copy number variation (CNV) patterns, which may further improve the preoperative classification. Design: Our study cohorts included benign follicular adenomas (FAs), classic papillary thyroid carcinomas (PTCs), and follicular variant PTCs (FVPTCs), the three subtypes most commonly associated with inconclusive preoperative cytopathology. Setting: Tissue and FNA samples were obtained at an academic tertiary referral center. Patients: Cases were identified that underwent partial or complete thyroidectomy for malignant or indeterminate thyroid lesions between 2000 and 2008 and had adequate snap-frozen tissue. Interventions: Pairs of tumor tissue and matching normal thyroid tissue-derived DNA were compared using 550K single-nucleotide polymorphism arrays. Main Outcome Measure: Statistically significant differences in CNV patterns between tumor subtypes were identified. Results: Segmental amplifications in chromosomes (Ch) 7 and 12 were more common in FAs than in PTCs or FVPTCs. Additionally, a subset of FAs and FVPTCs showed deletions in Ch22. Weidentified the 5 CNV-associated genes best at discriminating between FAs and PTCs/FVPTCs, which correctly classified 90{\%} of cases. These 5 Ch12 genes were validated by quantitative genomic PCR and gene expression array analyses on the same patient cohort. The 5-gene signature was then successfully validated against an independent test cohort of benign and malignant tumor samples. Finally, we performed a feasibility study on matched FA-derived intraoperative FNA samples and were able to correctly identify FAs harboring the Ch12 amplification signature, whereas FAs without amplification showed a normal Ch12 signature. Conclusions: Thyroid tumor subtypes possess characteristic genomic profiles that may further our understanding of structural genetic changes in thyroid tumor subtypes and may lead to the development of new diagnostic biomarkers in FNA samples.",
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T1 - DNA copy number variations characterize benign and malignant thyroid tumors

AU - Liu, Yan

AU - Cope, Leslie

AU - Sun, Wenyue

AU - Wang, Yongchun

AU - Prasad, Nijaguna

AU - Sangenario, Lauren

AU - Talbot, Kristen

AU - Somervell, Helina

AU - Westra, William

AU - Bishop, Justin

AU - Califano, Joseph

AU - Zeiger, Martha

AU - Umbricht, Christopher

PY - 2013/3/1

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N2 - Context: Fine-needle aspiration (FNA) is the best diagnostic tool for preoperative evaluation of thyroid nodules but is often inconclusive as a guide for surgical management. Objective: Our hypothesis was that thyroid tumor subtypes may show characteristic DNA copy number variation (CNV) patterns, which may further improve the preoperative classification. Design: Our study cohorts included benign follicular adenomas (FAs), classic papillary thyroid carcinomas (PTCs), and follicular variant PTCs (FVPTCs), the three subtypes most commonly associated with inconclusive preoperative cytopathology. Setting: Tissue and FNA samples were obtained at an academic tertiary referral center. Patients: Cases were identified that underwent partial or complete thyroidectomy for malignant or indeterminate thyroid lesions between 2000 and 2008 and had adequate snap-frozen tissue. Interventions: Pairs of tumor tissue and matching normal thyroid tissue-derived DNA were compared using 550K single-nucleotide polymorphism arrays. Main Outcome Measure: Statistically significant differences in CNV patterns between tumor subtypes were identified. Results: Segmental amplifications in chromosomes (Ch) 7 and 12 were more common in FAs than in PTCs or FVPTCs. Additionally, a subset of FAs and FVPTCs showed deletions in Ch22. Weidentified the 5 CNV-associated genes best at discriminating between FAs and PTCs/FVPTCs, which correctly classified 90% of cases. These 5 Ch12 genes were validated by quantitative genomic PCR and gene expression array analyses on the same patient cohort. The 5-gene signature was then successfully validated against an independent test cohort of benign and malignant tumor samples. Finally, we performed a feasibility study on matched FA-derived intraoperative FNA samples and were able to correctly identify FAs harboring the Ch12 amplification signature, whereas FAs without amplification showed a normal Ch12 signature. Conclusions: Thyroid tumor subtypes possess characteristic genomic profiles that may further our understanding of structural genetic changes in thyroid tumor subtypes and may lead to the development of new diagnostic biomarkers in FNA samples.

AB - Context: Fine-needle aspiration (FNA) is the best diagnostic tool for preoperative evaluation of thyroid nodules but is often inconclusive as a guide for surgical management. Objective: Our hypothesis was that thyroid tumor subtypes may show characteristic DNA copy number variation (CNV) patterns, which may further improve the preoperative classification. Design: Our study cohorts included benign follicular adenomas (FAs), classic papillary thyroid carcinomas (PTCs), and follicular variant PTCs (FVPTCs), the three subtypes most commonly associated with inconclusive preoperative cytopathology. Setting: Tissue and FNA samples were obtained at an academic tertiary referral center. Patients: Cases were identified that underwent partial or complete thyroidectomy for malignant or indeterminate thyroid lesions between 2000 and 2008 and had adequate snap-frozen tissue. Interventions: Pairs of tumor tissue and matching normal thyroid tissue-derived DNA were compared using 550K single-nucleotide polymorphism arrays. Main Outcome Measure: Statistically significant differences in CNV patterns between tumor subtypes were identified. Results: Segmental amplifications in chromosomes (Ch) 7 and 12 were more common in FAs than in PTCs or FVPTCs. Additionally, a subset of FAs and FVPTCs showed deletions in Ch22. Weidentified the 5 CNV-associated genes best at discriminating between FAs and PTCs/FVPTCs, which correctly classified 90% of cases. These 5 Ch12 genes were validated by quantitative genomic PCR and gene expression array analyses on the same patient cohort. The 5-gene signature was then successfully validated against an independent test cohort of benign and malignant tumor samples. Finally, we performed a feasibility study on matched FA-derived intraoperative FNA samples and were able to correctly identify FAs harboring the Ch12 amplification signature, whereas FAs without amplification showed a normal Ch12 signature. Conclusions: Thyroid tumor subtypes possess characteristic genomic profiles that may further our understanding of structural genetic changes in thyroid tumor subtypes and may lead to the development of new diagnostic biomarkers in FNA samples.

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