RAS Mutation Is an Early Event in the Development of the Follicular Variant of Papillary Carcinoma and May Predispose to Subsequent Genetic Alterations
B Deslouches, MN Nikiforova, L Niemeier, YE Nikiforov. University of Pittsburgh, Pittsburgh, PA
Background: The follicular variant of papillary thyroid carcinoma (FVPTC) is a common variant, which may be diagnostically challenging for pathologists. Histologically, these tumors frequently present with patchy, focally developed nucleic features of PTC intermixed with the areas of benign-appearing nuclei. The biology of these tumors is not fully defined, although about 40% of them have RAS mutations.
Design: We studied the distribution of RAS mutations in 8 FVPTC tumors with patchy expression of the nucleic features of PTC. In each tumor, five separate areas containing well-developed nucleic features and small, round, benign-appearing nuclei where separately microdissected and tested for RAS mutations. In addition, we used Affymetrix Genome-Wide Human SNP Array 6.0 analysis to determine the copy number change in 6 FVPTC and matched normal tissues.
Results: In each of the 8 cases studied, all areas within the tumor, including those with benign-appearing nuclei, were positive for RAS mutation, indicating that it represents an early event in tumor development. The SNP array analysis of 5 additional FVPTC with diffusely present nuclear features revealed on average 318 chromosomal regions of amplification and 124 regions of deletion per tumor. One of the frequently deleted region was on 21q21.1, which was previously found to be deleted in lung cancer. It contains the USP25 gene as well as several microRNA genes. One of those miRNAs is miR99a, which we found to be 4-fold downregulated in the RAS-positive FVPTC tumors.
Conclusions: These findings indicate that RAS mutation is an early event in the development of FVPTC and present in the tumor areas with no well developed nuclear features of PTC. The RAS-positive tumors appear to be prone to subsequent genetic alterations, including multiple amplifications and deletions that may involve carcinogenic genes and miRNAs.
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 47, Tuesday Afternoon