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. 2019 Oct 25:20:324-336.
doi: 10.1016/j.isci.2019.09.030. Epub 2019 Sep 26.

Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing

Raffaele Ciampi  1 , Cristina Romei  2 , Teresa Ramone  2 , Alessandro Prete  2 , Alessia Tacito  2 , Virginia Cappagli  2 , Valeria Bottici  2 , David Viola  2 , Liborio Torregrossa  3 , Clara Ugolini  3 , Fulvio Basolo  3 , Rossella Elisei  2
Affiliations

Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing

Raffaele Ciampi et al. iScience. .

Abstract

Sporadic Medullary Thyroid Carcinoma (sMTC) is a rare but aggressive thyroid tumor. RET and RAS genes are present in about 50%-80% of cases, but most of the remaining cases are still orphan of a genetic driver. We studied the largest series of sMTC by deep sequencing to define the mutational landscape. With this methodology we greatly reduced the number of RET- or RAS-negative cases and we confirmed the central role of RET and RAS mutations. Moreover, we highlighted the bad prognostic role of RET mutations in sMTC and consolidated the favorable prognostic role of RAS mutations. For the first time, we showed that the variant allele frequency represents an additional prognostic marker inside the group of RET-mutated sMTC.

Keywords: Biological Sciences; Cancer; Genomics.

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Conflict of interest statement

The authors declare that there are no conflicts of interest that could affect the impartiality of the reported research.

Figures

None
Graphical abstract
Figure 1
Figure 1
Mutational Landscape of sMTC Mutational profile of the 168 informative sMTC cases identified by NGS analysis. Each column corresponds to a single case. Genetic variations are listed on the left. The colored squares correspond to somatic mutations, whereas the black squares correspond to germline mutations, all validated by Sanger sequencing. Squares with a point-pattern represent mutations that were not validated by Sanger or not confirmed to be somatic or germline. See also Table S1.
Figure 2
Figure 2
Survival in RET- and RAS-Mutated sMTC Cases Kaplan-Meier curves showing survival in patients with sMTC harboring RET mutations or RAS mutations. The difference in the curves was statistically significant (log rank = 4.41; p = 0.035) and demonstrated that RET-positive cases have a higher probability to die of the disease.
Figure 3
Figure 3
Correlation of the Variant Allele Frequency with Tumor Size and Outcome of Patients with sMTC (A) Correlation between the tumor size (cm) and VAF of the driver mutation in sMTC. The comparison considered all mutations (A1), only RET mutations (A2), only the RET M918T mutation (A3), and only RAS mutations (A4). In all cases, except RAS-mutated cases, a statistically significant difference was observed (A1: p < 0.0001; A2: p < 0.0001; A3: p = 0.0013; A4: p = ns). (B) Correlation between the VAF value (%) of the driver mutations and outcome of patients when considering all mutations (B1), only RET mutations (B2), and only RAS mutations (B3). The differences between the outcome categories were significant between disease-free and metastatic patients in the former two cases (B1: p = 0.003; B2: p = 0.0047; ANOVA), whereas no difference was observed considering only RAS mutations (B3: p = ns). Data are represented as mean ± SEM.
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