Impact of Mutation Density and Heterogeneity on Papillary Thyroid Cancer Clinical Features and Remission Probability

Carla Colombo, Marina Muzza, Maria Carla Proverbio, Delfina Tosi, Davide Soranna, Chiara Pesenti, Stefania Rossi, Valentina Cirello, Simone De Leo, Nicola Fusco, Monica Miozzo, Gaetano Bulfamante, Leonardo Vicentini, Stefano Ferrero, Antonella Zambon, Silvia Tabano, Laura Fugazzola

Research output: Contribution to journalArticlepeer-review


Background: The need to integrate the classification of cancer with information on the genetic pattern has emerged in recent years for several tumors. Methods: The genomic background of a large series of 208 papillary thyroid cancers (PTC) followed at a single center was analyzed by a custom MassARRAY genotyping platform, which allows the simultaneous detection of 19 common genetic alterations, including point mutations and fusions. Results: Of the PTCs investigated, 71% were found to have pathognomonic genetic findings, with BRAF V600E and TERT promoter mutations being the most frequent monoallelic alterations (42% and 23.5%, respectively), followed by RET/PTC fusions. In 19.2% of cases, two or more point mutations were found, and the co-occurrence of a fusion with one or more point mutation(s) was also observed. Coexisting BRAF V600E and TERT promoter mutations were detected in a subgroup of aggressive PTCs (12%). A correlation between several aggressive features and mutation density was found, regardless of the type of association (i.e., only point mutations, or point mutations and fusions). Importantly, Kaplan-Meier curves demonstrated that mutation density significantly correlated with a higher risk of persistent disease. In most cases, the evaluation of the allelic frequencies normalized for the cancer cell content indicated the presence of the monoallelic mutation in virtually all tumor cells. A minority of cases was found to harbor low allelic frequencies, consistent with the presence of the mutations in a small subset of cancer cells, thus indicating tumor heterogeneity. Consistently, the presence of coexisting genetic alterations with different allelic frequencies in some tumors suggests that PTC can be formed by clones/subclones with different mutational profiles. Conclusions: A large mono-institutional series of PTCs was fully genotyped by means of a cost- and time-effective customized panel, revealing a strong impact of mutation density and genetic heterogeneity on the clinical features and on disease outcomes, indicating that an accurate risk stratification of thyroid cancer cannot rely on the analysis of a single genetic event. Finally, the heterogeneity found in some tumors warrants attention, since the occurrence of this phenomenon is likely to affect response to targeted therapies.

Original languageEnglish
Pages (from-to)237-251
Number of pages15
Issue number2
Publication statusPublished - Feb 1 2019


  • BRAF
  • heterogeneity
  • MassARRAY
  • NTRK1
  • Papillary thyroid carcinoma
  • TERT

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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