Tumor Genotype Determines Phenotype and Disease-related Outcomes in Thyroid Cancer

Abstract

Objectives To correlate thyroid cancer genotype with histology and outcomes. Background The prognostic significance of molecular signature in thyroid cancer (TC) is undefined but can potentially change surgical management. Methods We reviewed a consecutive series of 1510 patients who had initial thyroidectomy for TC with routine testing for BRAF, RAS, RET/PTC, and PAX8/PPARG alterations. Histologic metastatic or recurrent TC was tracked for 6 or more months after oncologic thyroidectomy. Results Papillary thyroid cancer (PTC) was diagnosed in 97% of patients and poorly differentiated/anaplastic TC in 1.1%. Genetic alterations were detected in 1039 (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 (51%) and lymph node metastasis (46%). Conversely, RAS-positive PTC was commonly follicular variant (87%), with infrequent extrathyroidal extension (4.6%) and lymph node metastasis (5.6%). BRAFV600E and RET/PTC-positive PTCs were histologically similar. Analogously, RAS and PAX8/PPARG-positive PTCs were histologically similar. Compared with RAS or PAX8/PPARG-positive TCs, BRAFV600E or RET/PTC-positive TCs were more often associated with stage III/IV disease (40% vs 15%, P < 0.001) and recurrence (10% vs 0.7%, P < 0.001; mean follow-up 33 ± 21 mo). Distant metastasis was highest in patients with RET/PTC-positive TC (10.8%, P = 0.02). Conclusions In this large study of prospective mutation testing in unselected patients with TC, molecular signature was associated with distinctive phenotypes including cancers, with higher risks of both distant metastasis and early recurrence. Preoperative genotype provides valuable prognostic data to appropriately inform surgery.

Papillary Thyroid Carcinoma: Association Between Germline DNA Variant Markers and Clinical Parameters

“…The same variants also displayed a higher OR for fvPTC compared with cPTC. Of note, fvPTC was recently reported to be associated with infrequent ETE and lymph node metastases (31). This finding coincides with the data showing stronger association of rs116909374 and rs944289 with fvPTC and, at the same time, a negative association with lymph node and distant metastases.…”

“…Several reports have shown that a somatic mutation in BRAF V600E is associated with a higher recurrence rate in PTC and may be useful in predicting the risk of metastases. In a recent publication, 1510 patients with thyroid cancer (97% had PTC) underwent routine molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPARG alterations with postsurgical follow-up tracking metastases and recurrence of the disease (31). It was shown that BRAF V600E -positive PTC cases have a higher metastatic rate, while RAS-positive cases are predominately fvPTC with infrequent ETE and lymph node metastasis.…”

NGS based identification of mutational hotspots for targeted therapy in anaplastic thyroid carcinoma

“…In follicular-cell derived thyroid carcinoma RET mutations are generally rare events [41]. In a previous report RET gene variations were found in 1/22 (4.5%) ATC investigated [5].…”

Preoperative detection of RAS mutation may guide extent of thyroidectomy

“…10 Most RAS mutations have correlated to histologically low-grade FVPTC, but they also occur in other cancer types including FTC, poorly differentiated, and anaplastic thyroid cancer, and even medullary thyroid cancer. 9,11,12 …”