Different Mutation Profile and Allele Frequency Detected by NGS Distinguish Subgroups of Sporadic Medullary Thyroid Carcinomas Based on Tumor Size

    About 60% of sporadic Medullary Thyroid Carcinomas (sMTC) harbour somatic mutations in RET and RAS while 40% has no mutations. Aim of this project was to evaluate differences of mutation distribution and frequency according to tumor size.

    133 sMTC were divided in 4 groups according to tumor size (cm) : A (x<1); B (1<x<2); C  (2<x<3); D (x>3) and they were correlated with the presence of somatic mutations that was previously evaluated by NGS target sequencing. 53.4% of cases harbored RET mutations, 26.3% RAS mutations and 20.3% were negative. Mean mutation allele frequency (AF) was also correlated  with the tumor size in the 4 groups.

    The distribution of RET and RAS mutations was significantly different in the 4 group (P<0.0001): the rate of RET mutations was increasing in larger tumors: 35.3% (A), 51.1% (B), 64.3% (C); 70.8% (D); RAS mutations were lower in larger tumors: 29.4% (A), 31.2% (B), 21.4% (C); 16.7% (D) as well as in negative cases: 35.3% (A), 17% (B), 14.3% (C); 12.5% (D). Mean AF of RET mutations was also increasing according to tumor size (P=0.0001): 25.1% (A), 29.5% (B), 42.4% (C); 46.4% (D). No difference in RAS mutations AF was observed.

    The overall rate of RET and RAS somatic mutations is lower in smaller MTCs and significantly increases in larger tumors. Statistically significant difference in RET mutations allele frequency shows that smaller tumors are less clonal and more heterogeneous when compared to larger tumors.


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