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Tumor Genotype Determines Phenotype and Disease-Related Outcomes in Thyroid Cancer: A Study of 1,510 Patients
Linwah Yip*, Marina N. Nikiforova*, Jenny Yoo*, Kelly L. McCoy*, Michael T. Stang*, Kristina J. Nicholson*, Michaele J. Armstrong*, Steven P. Hodak*, Robert L. Ferris*, Yuri E. Nikiforov*, Sally E. Carty
University of Pittsburgh, Pittsburgh, PA

OBJECTIVE(S):
The prognostic significance of molecular signature in thyroid cancer (TC) is undefined but is expected to markedly change surgical management. Our aim is to correlate TC genotype to histology and outcomes.
METHODS:
We reviewed a consecutive series of 1,510 patients who had initial thyroidectomy for TC from 2/07-6/13 with routine testing for BRAF, RAS, RET/PTC, and PAX8/PPARg genetic alterations. Histologic metastatic or recurrent TC was tracked ≥6 months after oncologic thyroidectomy.
RESULTS:
Papillary thyroid cancer (PTC) was diagnosed in 97%, and poorly-differentiated/anaplastic TC in 0.9%. Genetic alterations were detected in 1,039 (70%); the most common mutations were BRAFV600E (644/1039, 62%) and RAS isoforms (323/1039, 31%). BRAFV600E-positive PTC was often conventional or tall-cell variant (58%), with frequent extrathyroidal extension (ETE, 51%) and lymph node metastasis (LNM, 46%). Conversely, RAS-positive PTC was commonly follicular-variant (87%), with infrequent ETE (4.6%) and LNM (5.6%). BRAFV600E- and RET/PTC-positive PTCs were histologically similar. Analogously, RAS- and PAX8/PPARg-positive PTCs were histologically similar. Compared to RAS- or PAX8/PPARg-positive TC, the TC expressing BRAFV600E or RET/PTC were more often associated with TNM stage III/IV at presentation (40% v. 15%, p<.001) and early recurrence (10% v. 0.7%, p <.001; mean followup 33±21months). Distant metastasis was highest in patients with RET/PTC-positive TC (10.8%, p=.02).
CONCLUSIONS:
In this unique, large study of prospective mutation testing in unselected patients with thyroid cancer, molecular signature predicted distinctive tumor phenotypes including TC with higher risks of both distant metastasis and early recurrence. Preoperative genotype provides valuable prognostic data to appropriately inform surgical care.


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