A Subset of Papillary Thyroid Carcinomas Contain KRAS Mutant Subpopulations at Levels Above Normal Thyroid

The molecular pathogenesis of papillary thyroid carcinoma (PTC) is largely attributed to chromosomal rearrangements and point mutations in genes within the MAPK pathway (i.e., BRAF and RAS). Despite KRAS being the 6th most frequently mutated gene for all cancers, the reported frequency in thyroid cancer is only 2%. This may be due, in part, to the use of insensitive mutation detection methods such as DNA sequencing. Therefore, using the sensitive and quantitative ACB-PCR approach, we quantified KRAS codon 12 GGTGAT and GGTGTT mutant fraction (MF) in 20 normal thyroid tissues, 17 primary PTC, 2 metastatic PTC, and 1 anaplastic thyroid carcinoma. We observed measurable levels of KRAS codon 12 GAT or GTT mutation in all normal thyroid tissues. For PTCs, 29.4% and 35.3% had KRAS codon 12 GAT and GTT MF above the 95% upper confidence interval for the corresponding MFs in normal thyroid. The highest observed KRAS codon 12 GTT MFs were associated with tumors with follicular characteristics and relatively high levels of tumor necrosis. The results indicate KRAS mutant subpopulations are present in a large number of thyroid tumors, a fact previously unrecognized. The presence of KRAS mutation may indicate a tumor with an aggressive phenotype, thus directing the course of clinical treatment. (c) 2012 Wiley Periodicals, Inc.