IMPACT OF MUTATION DENSITY AND HETEROGENEITY ON PAPILLARY THYROID CANCER CLINICAL FEATURES AND REMISSION PROBABILITY.

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IMPACT OF MUTATION DENSITY AND HETEROGENEITY ON PAPILLARY THYROID CANCER CLINICAL FEATURES AND REMISSION PROBABILITY.

Thyroid. 2018 Dec 01;:

Authors: Colombo C, Muzza M, Proverbio MC, Tosi D, Soranna D, Pesenti C, Rossi S, Cirello V, De Leo S, Fusco N, Miozzo M, Bulfamante G, Vicentini L, Ferrero S, Zambon A, Tabano S, Fugazzola L

Abstract
BACKGROUND: The need to integrate the classification of cancer with information on the genetic pattern has emerged in recent years for several tumors.
PATIENTS AND METHODS: The genomic background of a large series of 208 papillary thyroid cancers (PTC) followed at a single Center was analysed by a custom MassARRAY genotyping platform (PTC-MA), which allows the simultaneous detection of 19 common genetic alterations including point mutations and fusions.
RESULTS: 71% of the PTCs was genetically classified, being BRAFV600E variant and TERT promoter mutations the most frequent heterozygous 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 ≥1 point mutation/s was also observed. Coexisting BRAFV600E 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 mutations' 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 heterozygous mutation in virtually all the 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 in some tumors of coexisting genetic alterations, with different allelic frequencies, 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 the disease outcome, 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 target-based drugs.

PMID: 30501571 [PubMed - as supplied by publisher]

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