DNA copy number variations characterize benign and malignant thyroid tumors.
BACKGROUND
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.


METHODS
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.


METHODS
Tissue and FNA samples were obtained at an academic tertiary referral center.


METHODS
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.


METHODS
Pairs of tumor tissue and matching normal thyroid tissue-derived DNA were compared using 550K single-nucleotide polymorphism arrays.


METHODS
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. We identified 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.
Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Yan
Y
Liu
Leslie
L
Cope
Wenyue
W
Sun
Yongchun
Y
Wang
Nijaguna
N
Prasad
Lauren
L
Sangenario
Kristen
K
Talbot
Helina
H
Somervell
William
W
Westra
Justin
J
Bishop
Joseph
J
Califano
Martha
M
Zeiger
Christopher
C
Umbricht
D018263:Adenocarcinoma, Follicular / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018249:Adenoma, Oxyphilic; D018254:Adenomatoid Tumor / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000328:Adult; D044963:Biopsy, Fine-Needle; D056915:DNA Copy Number Variations / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D023281:Genomics / Q000379:methods / Q000592:standards; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011300:Preoperative Care / Q000379:methods; D015203:Reproducibility of Results; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D013965:Thyroidectomy; D059467:Transcriptome