ABSTRACT
BACKGROUND: Inactivation of DNA mismatch repair (MMR) and the resulting microsatellite instability (MSI) are frequently observed in endometrial, stomach, and colorectal cancers, as well as more rarely in other solid tumor types. The prevalence of MSI in thyroid cancer has not been explored in depth, although recent studies utilizing data from large cancer sequencing efforts such as The Cancer Genome Atlas indicate that MSI is absent or at least very rare in the most common and most well studied histologic subtype, papillary thyroid carcinoma. This study aimed to determine the prevalence of MSI in thyroid cancer by using a large series comprising all major histological subtypes. METHODS: A total of 485 thyroid cancer patients were screened for MSI/MMR deficiency, including all major histologic subtypes (195 papillary thyroid carcinoma, 156 follicular thyroid carcinoma [FTC], 50 anaplastic thyroid carcinoma, 65 medullary thyroid carcinoma, and 17 poorly differentiated thyroid carcinomas) by using a combination of polymerase chain reaction-based detection, immunohistochemistry, and next-generation sequencing. RESULTS: A total of four tumors were MSI-high and had loss of MMR protein expression, all of which were from FTC patients. Whole-exome sequencing was performed on two MSI-high FTCs and revealed a hemizygous loss of function mutation in MSH2 in one tumor. CONCLUSIONS: Based on these data, it is estimated that the overall prevalence of MSI in FTC is 2.5%, and MSI is either entirely absent or rare in other histology subtypes of thyroid carcinoma. These findings highlight the importance of testing for MSI in FTC.
Subject(s)
Adenocarcinoma, Follicular/genetics , Biomarkers, Tumor/genetics , DNA Mismatch Repair , Microsatellite Instability , MutS Homolog 2 Protein/genetics , Thyroid Neoplasms/genetics , Adenocarcinoma, Follicular/pathology , Genetic Predisposition to Disease , Hemizygote , Humans , Loss of Heterozygosity , Mutation , Phenotype , Risk Factors , Thyroid Neoplasms/pathologyABSTRACT
FHIT is a genome caretaker gene that is silenced in >50% of cancers. Loss of Fhit protein expression promotes accumulation of DNA damage, affects apoptosis and epithelial-mesenchymal transition, though molecular mechanisms underlying these alterations have not been fully elucidated. Initiation of genome instability directly follows Fhit loss and the associated reduced Thymidine Kinase 1 (TK1) protein expression. The effects on TK1 of Fhit knockdown and Fhit induction in the current study confirmed the role of Fhit in regulating TK1 expression. Changes in Fhit expression did not impact TK1 protein turnover or transcription from the TK1 promoter, nor steady-state levels of TK1 mRNA or turnover. Polysome profile analysis showed that up-regulated Fhit expression resulted in decreased TK1 RNA in non-translating messenger ribonucleoproteins and increased ribosome density on TK1 mRNA. Fhit does not bind RNA but its expression increased luciferase expression from a transgene bearing the TK1 5'-UTR. Fhit has been reported to act as a scavenger decapping enzyme, and a similar result with a mutant (H96) that binds but does not cleave nucleoside 5',5'-triphosphates suggests the impact on TK1 translation is due to its ability to modulate the intracellular level of cap-like molecules. Consistent with this, cells expressing Fhit mutants with reduced activity toward cap-like dinucleotides exhibit DNA damage resulting from TK1 deficiency, whereas cells expressing wild-type Fhit or the H96N mutant do not. The results have implications for the mechanism by which Fhit regulates TK1 mRNA, and more broadly, for its modulation of multiple functions as tumor suppressor/genome caretaker.
Subject(s)
Acid Anhydride Hydrolases/metabolism , Gene Expression Regulation, Enzymologic/physiology , Neoplasm Proteins/metabolism , Promoter Regions, Genetic/physiology , Thymidine Kinase/biosynthesis , Acid Anhydride Hydrolases/genetics , Amino Acid Substitution , Cell Line, Tumor , Humans , Mutation, Missense , Neoplasm Proteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Thymidine Kinase/geneticsABSTRACT
PURPOSE: To evaluate the effect of trimodal image fusion using computed tomography (CT), magnetic resonance imaging (MRI) and (11)C-methionine positron emission tomography (MET-PET) for gross tumor volume delineation in fractionated stereotactic radiotherapy of skull base meningiomas. PATIENTS AND METHODS: In 32 patients with skull base meningiomas, the gross tumor volume (GTV) was outlined on CT scans fused to contrast-enhanced MRI (GTV-MRI/CT). A second GTV, encompassing the MET-PET positive region only (GTV-PET), was generated. The additional information obtained by MET-PET concerning the GTV delineation was evaluated using the PET/CT/MRI co-registered images. The sizes of the overlapping regions of GTV-MRI/CT and GTV-PET were calculated and the amounts of additional volumes added by the complementing modality determined. RESULTS: The addition of MET-PET was beneficial for GTV delineation in all but 3 patients. MET-PET detected small tumor portions with a mean volume of 1.6 +/- 1.7 cm(3) that were not identified by CT or MRI. The mean percentage of enlargement of the GTV using MET-PET as an additional imaging method was 9.4% +/- 10.7%. CONCLUSIONS: Our data have demonstrated that integration of MET-PET in radiotherapy planning of skull base meningiomas can influence the GTV, possibly resulting in an increase, as well as in a decrease.
