Activating mutations of genes coding for two different tyrosine kinase receptor, either RET or NTRK1 (also named TRKA), as well as of RAS or BRAF gene are associated with human thyroid papillary carcinoma (PTC). RET or NTRK1 protooncogene encodes a cell-surface transmembrane tyrosine kinase receptor with nerve growth factor as its lignand. Oncogenic potential of these two genes in thyrocytes results from replacement of their 5' portion by regulatory parts of other genes, leading to constitutive activation of their tyrosine kinase activity. The four reported oncogenic rearrangements of NTRK1 (TRK) are the consequences of fusion of its tyrosine kinase domain with one of the three genes (TPM3 gene, TPR gene, TFG gene). In our previous study, a PTC sample was found to express the NTRK1 tyrosine kinase domain without harboring NTRK1 rearrangement. We, therefore, assumed that there might have a novel NTRK1 rearrangement in this sample. 5¡¦RACE strategy was employed to clone the unknown 5¡¦end. Sequence of the cloned DNA fragment demonstrated that it is an aberrant transcription product containing an unspliced intron 9. In addition, the variant of NTRK1 wild type termed TRKA¢¹, which lacks exon 9, was also detected in this particular specimen. We conclude that amplification of TK domain of NTRK1 may serve as a rapid screening method for the presence of NTRK1-related transcript in PTCs.
Mutations of the BRAF protein serine/threonine kinase gene have recently been identified in a variety of human cancers, especially in melanoma and papillary thyroid carcinomas. Among benign and malignant thyroid tumors, BRAF V599E mutations were reported to be restricted to papillary carcinomas. In this study, we analyzed mutations of BRAF in conjunction with our previous studies on RAS, RET rearrangement and NTRK1 rearrangement in PTCs to investigate genetic alterations in the RAS/RAF/MEK/MAPK kinase pathway. BRAF V599E mutations were detected in 49 of 105 (47%) PTCs but not in other type of thyroid tumor. There was no overlap between papillary carcinomas harboring RET rearrangement, NTRK1 rearrangement and BRAF mutations. Correlation between BRAF mutations and various clinicopathological parameters in 101 papillary carcinomas did not reveal any association with age, sex, tumor size, cervical lymph node metastasis, extrathyroidal extension, distant metastases and clinical stage. We conclude that BRAF mutations are restricted to papillary carcinomas in thyroid tumor. The overall frequencies in our study are in line with data previously reported. In Taiwan, BRAF mutation is the most prevalent oncogene in papillary thyroid carcinomas so far identified.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0715104-104146 |
| Date | 15 July 2004 |
| Creators | Li, Chun-Liang |
| Contributors | Rue-Tsuan Liu, Chao-Cheng Huang, Jiin-Tsuey Cheng, Chung-Lung Cho |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | Cholon |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0715104-104146 |
| Rights | withheld, Copyright information available at source archive |
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