Relationship of Mitogen-Activated Protein Kinase and Stromal Reaction in Sporadic Thyroid Malignancies: Role of MAP3K8 in Papillary Carcinomas.
Jane Moorhead, Ringo Lam, Lok Lam, Alfredo Blanes, Salvador J Diaz-Cano. King's College Hospital, London, United Kingdom; University of Malaga School of Medicine, Spain
Background: The relationship between kinetic features, mitogen-activated protein (MAP) kinase and the types of stromal reaction are not known in common thyroid malignancies, both follicular and parafollicular.
Design: We selected sporadic thyroid carcinomas including papillary (PTC, 29), follicular carcinomas (FTC, 15 minimally-invasive and 15 widely-invasive), adenomas (FTA, 19), medullary (MTC, 18) and anaplastic carcinomas (ATC, 10) (WHO criteria) to analyze in a low-density selective cDNA array (LD-SelGEA) for proliferation-apoptosis pathways (MKI67, ERK1, CASP3, MAP3K8, AKT1, CHUK, MAP2K4, MAP3K14, NFKB1, TRAF2), and stromal-inflammatory reaction types (CDH11, SDC1, SPARC, MMP11, CSF1, CD68, CD163, and FCGR2). Total RNA was extracted, cleaned from normal and neoplastic tissues (RNeasy columns), first-strand cDNA synthesized using T7-(dT24)-oligomer and used as template for cRNA synthesis. The cRNA was fragmented, Cy3-/Cy5-labeled, and hybridized to LD-SelGEA noncompetitively, cross-validating the results (expression factor>2, significance<0.01). Variables were studied regarding the histological diagnosis and common molecular profile: BRAF and RAS mutation, RET/PTC and PAX8/PPAR fusion gene, and TP53 LOH/mutation and combinations. Significant variables were then tested on tissue sections by immunohistochemistry.
Results: Statistical significant differences (expression factor>2 at least) were observed for MKI67 (down-regulation in MTC, along with ERK1), MAPK3K8 (up-regulated in PTC and ATC), and CDH11 (up-regulated in PTC). Down-regulated genes throughout the series regardless of the diagnosis included: TRAF2, MMP11, CSF1, CD68, and FCGR2. Genes with no significant differences comprised: CASP3, CHUK, MAP2K4, NFKB1, SDC1, SPARC, CD163. No significant differences were observed for each diagnostic group by the DNA genotype (point mutations, fusion genes and LOH).
Conclusions: MAP3K8 upregulation in PTC results in activation of MAP kinase and JNK kinase pathways that promote both (a) T lymphocyte activation contributing to the presence of the lymphocytic infiltrate and (b) a typical stromal reaction of desmoid-type fibromatosis. No CSF1 macrophage response characterizes thyroid malignancies, and the types of stromal reactions are genotype independent.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 42, Tuesday Afternoon