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Published on: August 23, 2019
Differential gene expression of medullary thyroid carcinoma reveals specific markers associated with genetic
Agnieszka Maliszewska1, Luis J Leandro-Garcia, Esmeralda Castelblanco
1Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Center CNIO, Madrid, Spain.
Abstract:
Medullary thyroid carcinoma accounts for 2% to 5% of thyroid malignancies, of which 75% are sporadic and the remaining 25% are hereditary and related to multiple endocrine neoplasia type 2 syndrome. Despite a genotype-phenotype correlation with specific germline RET mutations, knowledge of pathways specifically associated with each mutation and with non-RET-mutated sporadic MTC remains lacking. Gene expression patterns have provided a tool for identifying molecular events related to specific tumor types and to different clinical features that could help identify novel therapeutic targets. Using transcriptional profiling of 49 frozen MTC specimens classified as RET mutation, we identified PROM1, LOXL2, GFRA1, and DKK4 as related to RET(M918T) and GAL as related to RET(634) mutation. An independent series of 19 frozen and 23 formalin-fixed, paraffin-embedded (FFPE) MTCs was used for validation by RT-qPCR. Two tissue microarrays containing 69 MTCs were available for IHC assays. According to pathway enrichment analysis and gene ontology biological processes, genes associated with the MTC(M918T) group were involved mainly in proliferative, cell adhesion, and general malignant metastatic effects and with Wnt, Notch, NFκB, JAK/Stat, and MAPK signaling pathways. Assays based on silencing of PROM1 by siRNAs performed in the MZ-CRC-1 cell line, harboring RET(M918T), caused an increase in apoptotic nuclei, suggesting that PROM1 is necessary for survival of these cells. This is the first report of PROM1 overexpression among primary tumors.
Insights
This study identifies specific gene expression patterns in medullary thyroid carcinoma (MTC) linked to RET mutations. PROM1 overexpression in RET(M918T) MTC suggests it is crucial for tumor cell survival and a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Medullary thyroid carcinoma (MTC) comprises 2-5% of thyroid cancers.
- While genotype-phenotype correlations exist for RET mutations in MTC, specific pathway knowledge is limited.
- Gene expression profiling offers insights into tumor molecular events and potential therapeutic targets.
Purpose of the Study:
- To identify gene expression patterns associated with specific RET mutations in MTC.
- To explore the functional role of identified genes in MTC pathogenesis.
- To discover novel therapeutic targets for MTC.
Main Methods:
- Transcriptional profiling of 49 MTC specimens with RET mutations.
- Validation using RT-qPCR on independent MTC cohorts (n=42).
- Immunohistochemistry (IHC) on tissue microarrays (n=69).
- Pathway enrichment and gene ontology analysis.
- Functional assays using siRNA to silence PROM1 in MTC cell lines.
Main Results:
- PROM1, LOXL2, GFRA1, and DKK4 identified as related to RET(M918T) mutation.
- GAL gene identified as related to RET(634) mutation.
- Genes associated with MTC(M918T) involve proliferation, cell adhesion, metastasis, and Wnt, Notch, NFκB, JAK/Stat, MAPK pathways.
- PROM1 silencing in MTC cells increased apoptosis, indicating its role in cell survival.
- First report of PROM1 overexpression in primary MTC tumors.
Conclusions:
- Specific gene expression profiles correlate with distinct RET mutations in MTC.
- PROM1 is overexpressed in RET(M918T) MTC and is essential for tumor cell survival.
- PROM1 represents a potential therapeutic target for MTC.
