Impact of Mutation Density and Heterogeneity on Papillary Thyroid Cancer Clinical Features and Remission Probability

BACKGROUND: The need to integrate the classification of cancer with information on the genetic pattern has emerged in recent years for several tumors. METHODS: The genomic background of a large series of 208 papillary thyroid cancers (PTC) followed at a single center was analyzed by a custom MassARRAY genotyping platform, which allows the simultaneous detection of 19 common genetic alterations, including point mutations and fusions. RESULTS: Of the PTCs investigated, 71% were found to have pathognomonic genetic findings, with BRAFV600E and TERT promoter mutations being the most frequent monoallelic alterations (42% and 23.5%, respectively), followed by RET/PTC fusions. In 19.2% of cases, two or more point mutations were found, and the co-occurrence of a fusion with one or more point mutation(s) was also observed. Coexisting BRAFV600E and TERT promoter mutations were detected in a subgroup of aggressive PTCs (12%). A correlation between several aggressive features and mutation density was found, regardless of the type of association (i.e., only point mutations, or point mutations and fusions). Importantly, Kaplan-Meier curves demonstrated that mutation density significantly correlated with a higher risk of persistent disease. In most cases, the evaluation of the allelic frequencies normalized for the cancer cell content indicated the presence of the monoallelic mutation in virtually all tumor cells. A minority of cases was found to harbor low allelic frequencies, consistent with the presence of the mutations in a small subset of cancer cells, thus indicating tumor heterogeneity. Consistently, the presence of coexisting genetic alterations with different allelic frequencies in some tumors suggests that PTC can be formed by clones/subclones with different mutational profiles. CONCLUSIONS: A large mono-institutional series of PTCs was fully genotyped by means of a cost- and time-effective customized panel, revealing a strong impact of mutation density and genetic heterogeneity on the clinical features and on disease outcomes, indicating that an accurate risk stratification of thyroid cancer cannot rely on the analysis of a single genetic event. Finally, the heterogeneity found in some tumors warrants attention, since the occurrence of this phenomenon is likely to affect response to targeted therapies

Are pre-miR-146a and PTTG1 associated with papillary thyroid cancer?

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, with a steadily increasing incidence in the last few decades worldwide. The predisposition to developing this carcinoma by the heterozygous state of rs2910164 within the precursor of the miR-146a has been reported, but recently not confirmed. Interestingly, on the same chromosome, almost 50\u200akb separate the pre-miR-146a from the pituitary tumor-transforming gene 1 (PTTG1), a proto-oncogene involved in several tumors, including thyroid cancers. In this study, we analyzed, using a case-control design, the genetic association between PTC and the genomic region encompassing pre-miR-146a rs2910164 and PTTG1 rs1862391 and rs2910202. We enrolled 307 affected patients and 206 healthy controls. The possible presence of thyroid nodules in controls was excluded by ultrasonography. All the cases were submitted to single-nucleotide polymorphism (SNP) genotyping of pre-miR-146a and PTTG1, and risk association analyses were carried out. The genotypic and allelic frequencies of pre-miR-146a rs2910164 were not statistically different in the patients and controls, and this SNP was not in linkage disequilibrium with the investigated PTTG1 SNPs. Consistently, meta-analyses, the first including all the affected cases published to date, did not confirm the previously reported association of the heterozygous CG genotype with PTC. The PTTG1 SNPs exhibited the same allelic frequency in the patients and controls and were not associated with the disease. In conclusion, in a well-selected Italian population, neither pre-miR-146a rs2910164 nor PTTG1 rs1862391 and rs2910202 were found to be associated with the risk of developing PTC

Fetal Microchimeric Cells in Blood of Women with an Autoimmune Thyroid Disease

CONTEXT: Hashimoto's thyroiditis (HT) and Graves' disease (GD), two autoimmune thyroid diseases (AITD), occur more frequently in women than in men and show an increased incidence in the years following parturition. Persisting fetal cells could play a role in the development of these diseases. OBJECTIVE: Aim of this study was to detect and characterize fetal cells in blood of postpartum women with and without an AITD. PARTICIPANTS: Eleven patients with an AITD and ten healthy volunteers, all given birth to a son maximum 5 years before analysis, and three women who never had been pregnant, were included. None of them had any other disease of the thyroid which could interfere with the results obtained. METHODS: Fluorescence in situ hybridization (FISH) and repeated FISH were used to count the number of male fetal cells. Furthermore, the fetal cells were further characterized. RESULTS: In patients with HT, 7 to 11 fetal cells per 1.000.000 maternal cells were detected, compared to 14 to 29 fetal cells in patients with GD (p=0.0061). In patients with HT, mainly fetal CD8(+) T cells were found, while in patients with GD, fetal B and CD4(+) T cells were detected. In healthy volunteers with son, 0 to 5 fetal cells were observed, which was significantly less than the number observed in patients (p<0,05). In women who never had been pregnant, no male cells were detected. CONCLUSION: This study shows a clear association between fetal microchimeric cells and autoimmune thyroid diseases

Positive effect of fetal cell microchimerism on tumor presentation and outcome in papillary thyroid cancer

Studies on both circulating and tissue fetal cell microchimerism (FCM) favored its protective role in thyroid cancer, consistent with findings in other malignancies. Nevertheless, scanty data were available on the possible impact on the outcome of the disease. We demonstrated that FCM has a positive effect on thyroid cancer presentation and outcome. We also excluded that the better clinical features observed were due to the effect of pregnancy per se. In conclusion, FCM may have not only a protective role toward the onset of thyroid cancer, but also a positive effect on its progression. These findings give novel insights into the identification of the role of FCM in oncology and, consequently, in the potential therapeutic application of this physiological phenomenon

Novel insights into the link between fetal cell microchimerism and maternal cancers

INTRODUCTION: Fetal cell microchimerism (FCM) is defined as the persistence of fetal cells in the mother for decades after pregnancy without any apparent rejection. Fetal microchimeric cells (fmcs) engraft the maternal bone marrow and are able to migrate through the circulation and to reach tissues. In malignancies, the possible role of fmcs is still controversial, several studies advising a protective and repairing function, and other postulating a beneficial role in the progression of the disease. At the peripheral blood level, FCM is less frequently observed in women with several solid and hematological neoplasia with respect to healthy controls, suggesting a beneficial role in cancer surveillance. At the tissue level, fmcs were documented in neoplastic lesions of thyroid, breast, cervix, lung and melanoma, displaying epithelial, hematopoietic, mesenchymal and endothelial lineage differentiation. Fmcs expressing hematopoietic markers were hypothesized to have a role in the attack to neoplastic cells, whereas those expressing epithelial or mesenchymal antigens could be involved in repair and replacement of damaged cells. On the other hand, fetal cells showing an endothelial phenotype could have a role in tumor evolution and progression. The positive effect of FCM is supported by findings in animal models. CONCLUSIONS: This review provides an extensive overview of the link between fetal cell microchimerism and maternal cancers. Moreover, biological mechanisms by which fetal cell microchimerism is believed to modulate the protection against cancer development or tumor progression will be discussed, together with findings in animal models

Study of the performances of a fluidynamic actuator

Aim of this paper is presented a new methodology to study how different geometric parameters affect the performance of a hydraulic actuator. Preliminarily, the real working conditions of a hydraulic machine have been simulated by means of a CFD module. After, to test the reliability of the simulations, the obtained numerical results have been compared with the experimental data of a real prototype. This comparison demonstrates a good level of agreement between numerical and experimental results. Different simulations have been setup by modifying the actuator geometry and evaluating the efficiency of every analysed configuration. The results of this study give useful guidelines for the choice of the best geometry depending on the working conditions of the actuator

Fetal cell microchimerism in human cancers

The transfer of fetal cells into the maternal circulation occurs normally during pregnancy and the post-partum persistence of these cells in the maternal blood and tissues, known as fetal cell microchimerism, has been clearly demonstrated. However, the long-term consequences of this phenomenon are only beginning to be appreciated. In particular, whether microchimerism could be involved in the carcinogenetic process or whether fetal microchimeric cells could be able to differentiate in host tissues, participating in the maternal response to injury, is still matter of study. In this review, the possible role and the consequences of fetal cell microchimerism, as emerged from studies in animal models and in women with different types of cancer, will be presented

Fetal microchimerism as an explanation of disease

Fetal cell microchimerism is defined as the persistence of fetal cells in the mother after birth without any apparent rejection. Fetal microchimeric cells (FMCs) engraft into the maternal bone marrow for decades after delivery and are able to migrate to blood and tissues. This phenomenon was hypothesized to have a detrimental role in autoimmune diseases, but data are still controversial and debated. In malignant tumors, fetal cell microchimerism has been postulated to have a positive effect on tumor burden, although some evidence suggests that FMCs may be involved in neoplastic progression. At the peripheral level, circulating FMCs are less frequently detected in patients with thyroid cancer, breast cancer or other solid, hematologic malignancies than in healthy individuals, which suggests a protective role for fetal cell microchimerism. In tissues, FMCs have been found in tumor sections from malignancies such as thyroid, breast, cervix, lung cancers and melanomas and have been shown to differentiate into epithelial, hematopoietic, endothelial and mesenchymal cells. FMCs with hematopoietic differentiation have been postulated to have a role in destroying the tumor, whereas mesenchymal and epithelial cells could participate in repair processes. Endothelial cells, on the other hand, are believed to play a part in tumor progression. This Review provides an overview of the role of fetal cell microchimerism in autoimmune and benign or malignant nonautoimmune diseases. Moreover, the mechanisms by which fetal cell microchimerism is believed to modulate the protection against cancer or tumor progression will be discussed, together with future research directions