A Comprehensive Analysis ofMNG1,TCO1,fPTC,PTEN,TSHR, and TRKA in Familial Nonmedullary Thyroid Cancer: Confirmation of Linkage to TCO1

Bevan, Steve; Pal, Tuya; Greenberg, C. R.; Green, H.; Wixey, Julie A.; Bignell, Graham R.; Narod, Steven A.; Foulkes, William D.; Stratton, Michael R.; Houlston, Richard S.

doi:10.1210/jcem.86.8.7725

Cited by 55 publications

(11 citation statements)

References 18 publications

(14 reference statements)

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“…It can be speculated that there will be a higher chance of sporadic in FNMTC patients with one affected relative, which will significantly underestimate the true difference. At present, a few molecular genetic analyses have identified several predisposing genes to FNMTC (36,37,38); however, genetic testing is not available because the association between specific genes with FNMTC is still under dispute. The identification of FNMTC still relies on clinical data.…”

Section: Discussionmentioning

confidence: 99%

ENDOCRINE TUMOURS: Familial nonmedullary thyroid carcinoma is a more aggressive disease: a systematic review and meta-analysis

Wang

Cheng

et al. 2015

European Journal of Endocrinology

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Objective: There is controversy as to whether familial nonmedullary thyroid carcinoma (FNMTC) is more aggressive than sporadic NMTC (SNMTC). The aim of the study was to evaluate the biological characteristics of patients with FNMTC by a meta-analysis. Methods: Four databases (PubMed, EMBASE, the Cochrane library databases, and the Web of Science) were searched to identify studies published before September, 2014. All original studies that compared clinical characteristics and prognosis of patients with FNMTC and SNMTC were included. The pooled effect sizes of interesting parameters were calculated by odds ratio (OR), standard mean difference (SMD), or hazard ratio (HR). Results: Twelve studies with a total of 12 741 participants were included in this analysis. FNMTC patients had an increased rate of recurrence (ORZ1.72, 95% CI: 1.34 to 2.20) and decreased disease-free survival (DFS) (HRZ1.83, 95% CI: 1.34 to 2.52) in comparison with SNMTC patients. FNMTC possessed more aggressive biological behaviors, characterized by younger age at diagnosis (SMDZK0.91, 95% CI: K1.59 to K0.22), higher risk of multifocal (ORZ1.50, 95% CI: 1.32 to 1.71), bilateral (ORZ1.29, 95% CI: 1.00 to 1.66), extrathyroidal invasion (ORZ1.20, 95% CI: 1.02 to 1.41), and lymph node metastasis (ORZ1.18, 95% CI: 1.01 to 1.38). Conclusion: FNMTC is a more aggressive disease and possesses higher recurrence rate and lower DFS. More attention and careful consideration should be paid regarding the decision about treatment for patients with FNMTC.

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Section: Discussionmentioning

confidence: 99%

ENDOCRINE TUMOURS: Familial nonmedullary thyroid carcinoma is a more aggressive disease: a systematic review and meta-analysis

Wang

Cheng

et al. 2015

European Journal of Endocrinology

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“…By both genetic linkage and sequence mutation analyses, the MET proto‐oncogene was excluded as a candidate susceptibility gene because it is responsible for familial papillary renal neoplasia [15]. Other candidate genes such as RET, PTEN, and MNG1 have also been excluded in a multigenerational kindred with HNMTC associated with and without papillary renal neoplasia [9, 13, 20]. Canzian and colleagues have also reported another multigenerational French kindred with papillary thyroid cancer and multinodular goiter that the susceptibility gene mapped to chromosome 19p13.2 [11].…”

Section: Genetics Of Hnmtcmentioning

confidence: 99%

“…These include early age at presentation, reversed gender distribution, larger tumor size, tumor multicentricity, and aggressive tumor biology. In addition, several genetic linkage studies of some kindreds have identified possible chromosomal loci associated with HNMTC [9–16]. Statistical probability calculations using thyroid cancer incidence rates in the United States estimate that when three or more first‐degree family members are affected a familial predisposition is highly likely in over 94% of cases [17, 18].…”

Section: Classification Of Hnmtcmentioning

confidence: 99%

“…Some investigators have reported HNMTC in association with benign thyroid tumors, renal neoplasia, and non‐autoimmune hyperthyroidism (Table 2). Although, the susceptibility gene or genes have not yet been identified for HNMTC, linkage analysis studies have identified four chromosomal loci that are associated with the condition (Table 2) [9–16, 19]. Kindreds with HNMTC and renal papillary tumors have been found to have an autosomal dominant and age‐dependent incomplete penetrance, with women more commonly affected than men [15].…”

Section: Genetics Of Hnmtcmentioning

confidence: 99%

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Hereditary Non‐medullary Thyroid Cancer

Kebebew

2007

World j. surg.

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An estimated 5% of all non-medullary thyroid cancers are hereditary. If three or more first-degree relatives are affected, there is a greater than 94% chance that these cases are hereditary non-medullary thyroid cancer (HNMTC). Although, the susceptibility gene(s) for HNMTC has not been identified, there are enough epidemiologic studies and kindreds reported to suggest a hereditary predisposition to thyroid cancer. Until the susceptibility genes are identified, clinicians will have to rely on comprehensive history taking to identify at-risk families and clinically screen at-risk family members. When families are at risk for HNMTC, it is unclear whether neck examination and or neck ultrasound is most effective for screening. Hereditary non-medullary thyroid cancer is associated with more aggressive disease than sporadic HNMTC, especially in index cases, with higher rates of multicentric tumors, lymph node metastasis, and extrathyroidal invasion. Aggressive screening may benefit other members of the affected kindred because the outcome for the non-index cases is better. Although no studies have demonstrated any difference in mortality in patients with HNMTC versus sporadic disease, disease-free survival is shorter in HNMTC. Aggressive surgical and postoperative medical therapy is warranted in patients with HNMTC. It is likely that emerging molecular approaches may help identify the gene or genes involved in HNMTC which would have important clinical ramifications.

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“…Our previous work has shown that TSHR expression levels play important roles in maintaining the differentiation of thyroid cancer cells (11)(12)(13). Nevertheless, in some cases, TSHR expression has been reported to remain normal (14). Moreover, few loss-of-function TSHR mutations in DTC tissue have been reported.…”

Section: Introductionmentioning

confidence: 99%

Crosstalk Between Abnormal TSHR Signaling Activation and PTEN/PI3K in the Dedifferentiation of Thyroid Cancer Cells

Fěng

Han

et al. 2021

Front. Oncol.

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Iodide uptake and the metabolism of thyroid cells are regulated by thyrotropin (TSH)-TSH receptor (TSHR) signaling. Thus, it is necessary to elevate serum TSH levels by T4 withdraw or rTSH administration to facilitate radioiodide (131I) therapy for differentiated thyroid cancer (DTC). However, non-iodide-avid metastases of DTC which is dedifferentiated do not respond to stimulation by high levels of TSH, suggesting abnormal TSH-TSHR signal transduction in cancer cells. In addition, PI3K/AKT/mTOR signaling activation has been shown to be associated with the dedifferentiated phenotype of thyroid cancer, but the mechanism remains elusive. Therefore, in this study, we aimed to explore the role of abnormal TSH-TSHR signaling activation in regulating iodide uptake and cell mobility in thyroid cancer and its relationship with PI3K/AKT/mTOR signaling. We found that in thyroid cancer cells, TSH binds TSHR coupled to the Gα12/13 protein and then activates RhoA through interacting with leukemia associated RhoA guanine exchange factor (LARG). This results in a promigration tumorigenic phenotype independent of canonical TSHR-GαS signaling that regulates the expression of molecules involved in iodine uptake and metabolism. We observed that signaling pathways downstream of Gα12/13 signaling were increased, while that of Gαs signaling was decreased in thyroid cancer cells undergoing dedifferentiation compared to control cells following stimulation with different levels of TSH. PI3K/AKT/mTOR signaling activation enhanced Gα12/13 signaling through increasing LARG levels but also inhibited the expression of molecules downstream of Gαs signaling, including thyroid-specific molecules, and iodide uptake. In summary, our results demonstrate the noncanonical activation of TSH-TSHR signaling and its role in increasing the cell mobility and dedifferentiation of thyroid cancer through crosstalk with PI3K/AKT/mTOR signaling.

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A Comprehensive Analysis ofMNG1,TCO1,fPTC,PTEN,TSHR, and TRKA in Familial Nonmedullary Thyroid Cancer: Confirmation of Linkage to TCO1

Cited by 55 publications

References 18 publications

ENDOCRINE TUMOURS: Familial nonmedullary thyroid carcinoma is a more aggressive disease: a systematic review and meta-analysis

ENDOCRINE TUMOURS: Familial nonmedullary thyroid carcinoma is a more aggressive disease: a systematic review and meta-analysis

Hereditary Non‐medullary Thyroid Cancer

Crosstalk Between Abnormal TSHR Signaling Activation and PTEN/PI3K in the Dedifferentiation of Thyroid Cancer Cells

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