Mutation profile of differentiated thyroid tumours in an Australian urban population.

BACKGROUND: The majority of differentiated thyroid cancers are characterised by one of several point mutations or gene rearrangements. Limited data are available on the prevalence and clinical correlations of these mutations in the Australian population. AIMS: The aim of the present study was to characterise the mutation profile of differentiated thyroid tumours in the local population. METHODS: The study involved 148 patients with differentiated thyroid cancer. The following tumours were examined: 109 papillary carcinomas (PTC), 27 follicular carcinomas (FC) and 12 Hurthle cell carcinomas (HCC). Polymerase chain reaction (PCR) was performed for BRAF and RAS mutations (RNA and DNA) as well as for RET/PTC rearrangements and PAX8-PPARγ translocations (RNA). Clinicopathological parameters and outcome data were analysed according to BRAFV600E status in PTC and RAS mutation status in FC. RESULTS: BRAFV600E was identified in 74/109 (68%) PTC. BRAFV600E was not significantly correlated with clinicopathological features of aggressive disease. At a median follow up of 48 months, there was no significant difference between BRAFV600E and wild-type BRAF PTC with respect to the rates of nodal recurrence, distant metastases or disease-specific death. In FC, RAS mutations (five NRAS and three HRAS) were present in 8/27 (30%) tumours. RAS mutation was significantly associated with widely invasive histology (P = 0.01) and distant metastases (P = 0.01) on follow up. CONCLUSION: In the present study, BRAF mutation was not associated with negative prognostic indicators or adverse outcomes in PTC. RAS mutation was positively correlated with aggressive features in FC suggesting potential prognostic utility, although confirmation is required from larger studies.

Molecular characterization of sarcomatous change in a granulosa cell tumor.

Sarcomatous transformation of a granulosa cell tumor (GCT) is a rare event. We describe the development of a rapidly progressive sarcomatous change in a woman who had initially presented with a classical GCT. A first recurrence occurred 23 months after the initial diagnosis when she was treated with external beam radiotherapy to her pelvis. A second recurrence 76 months following her initial surgery was consistent with a GCT. At 92 months, she presented with a further recurrence, outside of the radiotherapy field. This last recurrence had a different histologic appearance with features of sarcomatous change. Molecular analysis, using both reverse transcription-polymerase chain reaction and complementary DNA microarrays, has been used to analyze tissue obtained before and after the observed change in the tumor. The data show that GCT-specific genes, such as inhibin alpha, estrogen receptor, and follicle-stimulating hormone receptor, have been downregulated in the sarcomatous change. Significant upregulation of genes associated with an inflammatory response was also noted in the sarcoma, and this was consistent with the presence of a marked inflammatory infiltrate seen on histopathology. This study represents the novel application of microarray technology and demonstrates the unexpected finding of expression of the fibroblast activation protein gene in normal ovary. Although tumors such as this may be targets for the novel fibroblast activating protein-directed chemotherapeutic monoclonal antibody sibrotuzumab, the finding of expression in the normal ovary suggests the need for caution.

Insulin-like growth factor, insulin-like growth factor-binding protein-4, and pregnancy-associated plasma protein-A gene expression in human granulosa cell tumors.

The insulin-like growth factor (IGF) system plays an important role in folliculogenesis. It is also thought to contribute to the pathogenesis of many cancers, including those of the ovarian epithelium. In the human follicle, the predominant IGF is IGF-II and its actions are modulated by insulin-like growth factor-binding protein-4 (IGFBP-4), the IGFBP-4 protease, and the pregnancy-associated plasma protein-A (PAPP-A). These peptide components are synthesized by the granulosa cells of the developing follicle. The aim of this study was to characterize the expression of these components of the IGF system in granulosa cell tumors (GCT) of the ovary. IGF-I, IGF-II, IGFBP-4, and PAPP-A gene expression was determined in a panel of GCT and compared to the levels in normal ovary and in epithelial ovarian tumors. Although both the IGF-I and IGF-II genes were expressed in the GCT, the levels were lower than in the other tissue groups. IGFBP-4 expression was also low in the GCT, whereas PAPP-A gene expression was highest in the GCT. These findings were unexpected given the prominent role this signaling system plays in normal granulosa cells. In conclusion, these observations suggest that the IGF system may have a limited role in the pathogenesis of GCT with PAPP-A subserving a function other than IGFBP-4 proteolysis.