Mutation profile and immunoscore signature in thymic carcinomas: An exploratory study and review of the literature

Abstract

Background: Significant efforts have been made to investigate the molecular pathways involved in thymic carcinogenesis. However, genetic findings have still not impacted clinical practice. The aim of this exploratory trial was to evaluate the immunoscore and molecular profile of a series of thymic carcinomas (TCs), correlating this data with clinical outcome.

Methods: Formalin-fixed, paraffin-embedded (FFPE) TC tissues were retrieved from our center archive. The immunoscore was evaluated according to Angell and Gallon. DNA was extracted from FFPE tumor samples and, when available, from adjacent histologically normal tissues. Next-generation sequencing (NGS) was performed targeting hotspot regions of 50 oncogenes and tumor suppressor genes.

Results: A series of 15 TCs were analyzed. After a median follow-up of 82.4 months, the median overall survival was 104.7 months. The immunoscore was >2 in 5/15 patients (33%). Among the investigated genes, absence of mutations was observed in 5/15 patients (33%), whereas three variants in 1/15 (6%) patient, two variants in 4/15 (26%) patients, and one variant in 5/15 patients (33%) were found. The most recurrently mutated genes were FGFR3 (five mutations) and CDKN2A (three mutations, two of which were nonsense). Patients with CDKN2A loss showed a statistically significantly worse survival (P = 0.0013), whereas patients with FGFR3 mutations showed a statistically significantly better survival (P = 0.048).

Conclusions: This study adds data to the few existing reports on the mutational landscape of TCs, providing the first comprehensive analysis to date. Here, we confirm the low rate of mutations in TCs and suggest FGFR3 and CDKN2A mutations as intriguing potential therapeutic targets.

Keywords: Germline mutation; immunoscore; next-generation sequencing; somatic mutation; thymic carcinoma.

Figure 1

Mutational landscape of thymic carcinomas (TCs): A literature review. (a) The Venn diagrams (drawn as proportional objects) represent each analyzed study ⁷ , ⁹ , ¹⁰ , ²⁴ : The outer circle represents the analyzed patient cohort (the total number of sequenced cases is indicated at the top), the inner circle corresponds to the subset of patients in whom no mutations were identified (the total number of patients as well as the corresponding percentage are reported) () Nonsense mutation () Frame Shift Ins () Frame Shift Del () In Frame Ins () In Frame Del () Nonstop mutation () Translation start site () Splice site () Missense mutation () 5'Flank () 3'Flank () 5'UTR () 3'UTR () RNA () Intron () IGR () Silent. (b) The waterfall plot describes the main results of the analyzed studies. On the left, the plot reports the list of the 41 mutated genes in TCs, together with the corresponding percentage of individuals carrying a mutation (in percentage calculations, only mutated individuals have been considered). The right plot shows the types of mutations in each tumor sample. The only sample showing two deleterious mutations in the same gene (ATM) is indicated by an arrow. The lower part of the figure shows the targeted region investigated in each sample and indicates the relevant study () Petrini et al., 2014 () Radovich et al., 2018 () Exome () Wang et al., 2014 () This article () 197 genes () Enkner et al., 2014 () Exome + 197 genes () 50 genes.