Combined Mutational and Clonality Analyses Support the Existence of Intra-Tumor Heterogeneity in Papillary Thyroid Cancer

Abstract

Despite its potential clinical impact, intra-tumor genetic heterogeneity (ITH) has been scantly investigated in papillary thyroid cancer (PTC). We studied ITH in PTC by combining, for the first time, data derived from the evaluation of the normalized allelic frequencies (NAF) of the mutation/s, using a customized MassARRAY panel, and those obtained by the HUMARA clonality assay. Among tumors with a single mutation, 80% of cases with NAF 50 ± 5% were clonal, consistent with the presence of a single mutated clone, while 20% of cases showed a polyclonal pattern, suggesting the presence of the same mutation in two or more clones. Differently, all cases with NAF < 45% were polyclonal. Among tumors with double mutation, cases with both mutations showing NAF 50 ± 5% were monoclonal, consistent with the presence of a single clone harboring both mutations. On the other hand, all cases with double mutation at NAF < 45% were polyclonal, indicating the presence of two clones with different mutations. Finally, no significant differences in the clinico-pathological characteristics were found between monoclonal and polyclonal tumors. In conclusion, the present study adds insights into the concept of ITH in PTC, which warrants attention because the occurrence of this phenomenon is likely to affect the response to targeted drugs.

Clinicopathological indicators for TERT promoter mutation in papillary thyroid carcinoma

“…Intratumoral heterogeneity might be another reason for variable TERT promoter mutation frequencies. Although PTC was believed to be monoclonal, recent studies suggest polyclonal nature of this tumour by demonstrating spatially different mutation or expression profile in the same tumour 25 . Last, various methods to detect TERT promoter mutation might have caused the discrepancy, because each testing method has a different limit of detection.…”

PPARγ Targets-Derived Diagnostic and Prognostic Index for Papillary Thyroid Cancer

“…Nevertheless, a 10-year disease-specific survival (DSS) by the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) defined stages I to IV ranging from 81% (stage IV) to 100% (stage II) [3]. Despite being considered as an indolent tumor with low occurrence of local invasion, recurrences and regional or distant metastases, PTC, similar to other types of cancer, show inter-and intra-tumoral heterogeneity with varying degree of genetic diversity, which could have a significant impact on prognosis and on the response to targeted therapy [4,5]. The existence of a small population of tumors having the more aggressive variants of PTC, with distinct clinical, pathological, and molecular features suggest the need for a robust predictive marker for patient stratification disease management [4][5][6].…”