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Francesco Facciolo
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MS08 - Management of Thymic Carcinoma (ID 71)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Thymoma/Other Thoracic Malignancies
- Presentations: 1
- Now Available
- Moderators:Enrico Ruffini, Giovannella Palmieri
- Coordinates: 9/09/2019, 14:00 - 15:30, Seoul (2007)
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MS08.04 - Novel Biomarkers for Thymic Carcinoma (Now Available) (ID 3484)
14:00 - 15:30 | Author(s): Francesco Facciolo
- Abstract
- Presentation
Abstract
Thymic carcinoma (TC), the rarer among Thymic Epithelial Tumors (TET), occur with an incidence rate of 0.2-0.5/million/yr. Difficulties in the evaluation of molecular aspects derive from the extreme rarity of these tumors. The Squamous cell carcinoma (SQCC) is the most frequently analyzed, however the other rarer histotypes could differ both in molecular pathogenesis and in clinical behaviour. The Cancer Genome Atlas Thymoma study (TCGA-THYM) in a series of ten TC cases including four SQCC, four undifferentiated carcinoma and both one large cell neuroendocrine carcinoma as well as one TC, NOS, identified a few genes rarely mutated, including KIT, HRAS, NRAS and TP53, reflecting the low mutational burden of these tumors (1). In the last years, only a limited number of TC has been investigated by other groups and only a limited number of relevant alterations has been identified. In addition to genomic events, however, epigenetic factors could contribute to TET carcinogenesis. Wang et al. in 2014 performed targeted sequencing of 197 cancer-associated genes in 78 advanced-stage TET patients, including 47 TC and 31 thymoma (THYM) cases. They reported that TC showed a higher incidence of somatic non-synonymous mutations than THYM. Moreover, they found that mutations of epigenetic regulatory genes involved in chromatin modification pathways are common in TC in comparison to THYM (2).
In the last years we have been interested in the characterization of genomic and epigenetic findings related to TET development. In our earlier microRNA (miR) study, we reported, among other findings, preliminary data on mature microRNAs differentially expressed in TC vs THYM, as revealed by microarray-based unsupervised clustering analysis. Among the differentially expressed miRs, 3 were validated by RT-qPCR (miR128, miR142-5p and miR-181c-5p) (3). By a different approach, we analyzed by Next Generation Sequencing (NGS) thirteen TC cases and one Atypical Type A thymoma case. The tissues derived from Formalin-fixed, paraffin embedded (FFPE) material including biopsies/surgical specimens of tumors and a single case of matched peritumoral thymus. The percentage of neoplastic cells was not < 70-80% of total cells. The DNA was extracted using the QIAcube and QIAamp DNA FFPE Tissue Kit (Qiagen, Valencia, CA) from microdissected 5 μm FFPE tissue sections. The NGS platform Ion S5 (Thermofisher) and the Ion AmpliSeq™Cancer Hotspot Panel v2 were used. This panel is designed to amplify 207 amplicons covering over 2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes. Libraries from Ion AmpliSeq Cancer Hotspot Panel v2 were prepared and sequenced by Ion Chef and S5 system. Data analysis was conducted by using the dedicated Ion Reporter Software. Among other genomic variants (polymorphysms and mutations were found in four cases), in one out of these four TC cases a KIT mutation (c.1900C>T; p.R634W, exon 13), already reported in TC, was identified. Moreover, a further KIT mutation ( c.1718C>T p.P573L, exon11) was found in a second case. In addition, a missense TP53 mutation ( c.824G>T; p.C275F), occurring in exon 8, was observed in a single case of TC, NOS. The patient harbouring a TC with this TP53 mutation had a R0 robotic-assisted thymectomy of a pT2 Thymic carcinoma (according to the 8th TNM edition), and after adjuvant chemotherapy and radiotherapy is alive and in complete remission with a follow-up of 22 months . The recent case of Atypical Type A thymoma showed a NOTCH1 c.4732_4734delGTG p.V1578del in exon 26 of uncertain significance.
Basing on the relatively few cases reported in the literature, analyzed by different techniques for their genomic alterations, it appears that the mutation status of TC is highly heterogeneous. In the cases examined so far by NGS we didn’t find recurrent genetic aberrations, but a variety of alterations. Each case, with the panel available, revealed either polymorphisms or, in few cases, mutations in cancer-associated genes, both oncogenic and oncosuppressor. Among the genes involved, both the KIT reported variants could be considered relevant for targeted therapy. Moreover, the tumor suppressor gene TP53 is already known for its importance and frequency of mutations particularly in TC. Moreira et al reported recurrent TP53 mutations with unfavorable prognostic value (4). The TP53 mutation found in one of our cases (previously reported in cases of SQCC of upper respiratory tract, in lung, head & neck and esophageal carcinoma) affects, among others, the DNA damage repair, the cell cycle and the apoptosis pathways. In human thymus, the Notch pathway, activated in thymic EC, is crucial to T cell differentiation; moreover the Notch signaling is also involved in hematological and in solid tumors. The NOTCH1 c.4732_4734delGTG p.V1578del in exon 26 we reported in a Atypical case A thymoma was already described in lymphoid tissues. The clinical and prognostic value of the genomic alterations we observed needs to be definied.
1) Radovich M, et al., The integrated genomic landscape of thymic epithelial tumors - Cancer Cell, 2018 Feb 12;33(2):244-258
2) Wang Y, et al., Mutations of epigenetic regulatory genes are common in thymic carcinomas - Sci Rep. 2014 Dec 8;4:7336
3) Ganci F, et al., MicroRNAs Expression Profiling of Thymic Epithelial Tumors - Lung Cancer 2014, 85 (2) 197–204
4) Moreira AL, et al, Massively parallel sequencing identifies recurrent mutations in TP53 in thymic carcinoma associated with poor prognosis - J Thorac Oncol. 2015 Feb;10(2):373-80
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