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.