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Published on: August 25, 2023
Transcriptome analysis in mouse tumors induced by Ret-MEN2/FMTC mutations reveals subtype-specific role in survival
D Engelmann1, D Koczan, P Ricken
1Department of Vectorology and Experimental Gene Therapy, University of Rostock, D-18055 Rostock, Germany.
Abstract:
Activating mutations in the Ret proto-oncogene are responsible for occurrence of multiple endocrine neoplasia (MEN) type 2A and 2B, and familial medullary thyroid carcinoma (FMTC). A striking genotype-phenotype correlation between the mutated RET codon and clinical manifestation implies that tumorigenesis is conditioned by the type of mutation. We investigated gene expression profiles between and within distinct MEN2 subtypes through whole-genome microarray analysis in tumors induced by NIH-3T3 cells transformed with defined RET-MEN2A (C609Y, C634R), MEN2B, (A883F, M918T), and FMTC (Y791F) mutations. Expression profiling identified a statistically significant modification of 1494 genes, 628 down- and 866 upregulated in MEN2B compared with MEN2A/FMTC tumors. By contrast, no obvious alterations were observed among individual MEN2B and MEN2A type mutations, or between MEN2A and FMTC. Functional clustering of differential genes revealed RET-MEN2B specific upregulation of genes associated with novel growth and survival pathways. Intriguingly, RET-MEN2A/FMTC-specific tumors were characterized by a considerable number of genes involved in the host antitumor immune response via stimulation of natural killer/T-cell proliferation, migration, and cytotoxicity, which were completely absent in RET-MEN2B related cancers. QPCR on tumors versus cultured NIH-RET cell lines demonstrated that they are largely attributed to the host innate immune system, whereas expression of CX3CL1 involved in leukocyte recruitment is exclusively RET-MEN2A/FMTC tumor cell dependent. In correlation, massive inflammatory infiltrates were apparent only in tumors carrying MEN type 2A/FMTC mutations, suggesting that RET-MEN2B receptors specifically counteract immune infiltration by preventing chemokine expression, which may contribute to the different clinical outcome of both subtypes.
Insights
Activating RET mutations drive multiple endocrine neoplasia (MEN) types 2A and 2B. MEN2B tumors show distinct gene expression, lacking immune response genes found in MEN2A/FMTC, impacting clinical outcomes.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Activating mutations in the Ret proto-oncogene cause multiple endocrine neoplasia (MEN) types 2A and 2B, and familial medullary thyroid carcinoma (FMTC).
- Distinct RET mutations correlate with specific clinical manifestations, suggesting mutation type influences tumorigenesis.
Purpose of the Study:
- To investigate gene expression profiles in tumors associated with different RET-MEN2 subtypes.
- To identify molecular differences underlying distinct clinical phenotypes in MEN2 subtypes.
Main Methods:
- Whole-genome microarray analysis of tumors from NIH-3T3 cells transformed with specific RET-MEN2A, MEN2B, and FMTC mutations.
- Quantitative PCR (QPCR) to validate gene expression in tumors and cell lines.
Main Results:
- Expression profiling revealed 1494 differentially expressed genes between MEN2B and MEN2A/FMTC tumors.
- MEN2B tumors showed upregulation of growth and survival pathways, while MEN2A/FMTC tumors exhibited genes involved in host antitumor immune response (NK/T-cell activation).
- Immune infiltrates and chemokine expression (CX3CL1) were observed in MEN2A/FMTC tumors but absent in MEN2B tumors, suggesting RET-MEN2B counteracts immune infiltration.
Conclusions:
- RET-MEN2B specific mutations are associated with distinct gene expression profiles favoring tumor growth and survival.
- RET-MEN2A/FMTC mutations stimulate host antitumor immunity, contrasting with the immune evasion seen in RET-MEN2B.
- These molecular differences in immune response and chemokine expression likely contribute to the varied clinical outcomes observed in MEN2 subtypes.
