Current Knowledge of Germline Genetic Risk Factors for the Development of Non-Medullary Thyroid Cancer

The thyroid is the most common site of endocrine cancer. One type of thyroid cancer, non-medullary thyroid cancer (NMTC), develops from follicular cells and represents approximately 90% of all thyroid cancers. Approximately 5%–15% of NMTC cases are thought to be of familial origin (FNMTC), which is defined as the occurrence of the disease in three or more first-degree relatives of the patient. It is often divided into two groups: Syndrome-associated and non-syndromic. The associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex and Werner syndrome. The hereditary factors contributing to the unfavorable course of FNMTC remain poorly understood; therefore, considerable effort is being expended to identify contributing loci. Research carried out to date identifies fourteen genes (DICER1, FOXE1, PTCSC2, MYH9, SRGAP1, HABP2, BRCA1, CHEK2, ATM, RASAL1, SRRM2, XRCC1, TITF-1/NKX2.1, PTCSC3) associated with vulnerability to FNMTC that are not related to hereditary syndromes. In this review, we summarize FNMTC studies to date, and provide information on genes involved in the development of non-syndromic familial non-medullary thyroid cancers, and the significance of mutations in these genes as risk factors. Moreover, we discuss whether the genetic polymorphism rs966423 in DIRC3 has any potential as a prognostic factor of papillary thyroid cancer.

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Familial non-medullary thyroid cancer: unraveling the genetic maze

Endocrine Related Cancer ◽

10.1530/erc-16-0067 ◽

2016 ◽

Vol 23 (12) ◽

pp. R577-R595 ◽

Cited By ~ 48

Author(s):

Samantha Peiling Yang ◽

Joanne Ngeow

Keyword(s):

Thyroid Cancer ◽

Medullary Thyroid Cancer ◽

Werner Syndrome ◽

Study Groups ◽

Cowden Syndrome ◽

Susceptibility Genes ◽

Carney Complex ◽

Medullary Thyroid ◽

Functional Studies ◽

Chromosomal Loci

Familial non-medullary thyroid cancer (FNMTC) constitutes 3–9% of all thyroid cancers. Out of all FNMTC cases, only 5% in the syndromic form has well-studied driver germline mutations. These associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex type 1, Werner syndrome and DICER1 syndrome. It is important for the clinician to recognize these phenotypes so that genetic counseling and testing can be initiated to enable surveillance for associated malignancies and genetic testing of family members. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. To date, 4 susceptibility genes have been identified (SRGAP1 gene (12q14), TITF-1/NKX2.1 gene (14q13), FOXE1 gene (9q22.33) and HABP2 gene (10q25.3)), out of which only the FOXE1 and the HABP2 genes have been validated by separate study groups. The causal genes located at the other 7 FNMTC-associated chromosomal loci (TCO (19q13.2), fPTC/ PRN (1q21), FTEN (8p23.1-p22), NMTC1 (2q21), MNG1 (14q32), 6q22, 8q24) have yet to be identified. Increasingly, gene regulatory mechanisms (miRNA and enhancer elements) are recognized to affect gene expression and FNMTC tumorigenesis. With newer sequencing technique, along with functional studies, there has been progress in the understanding of the genetic basis of FNMTC. In our review, we summarize the FNMTC studies to date and provide an update on the recently reported susceptibility genes including novel germline SEC23B variant in Cowden syndrome, SRGAP1 gene, FOXE1 gene and HABP2 genes in non-syndromic FNMTC.

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Ung thư biểu mô tuyến giáp không phải thể tủy mang tính gia đình

Vietnam Journal of Diabetes and Endocrinology ◽

10.47122/vjde.2019.33(2).4 ◽

2019 ◽

Author(s):

Hòa Trần

Keyword(s):

Thyroid Cancer ◽

Medullary Thyroid Cancer ◽

Carney Complex ◽

Early Age ◽

Susceptibility Loci ◽

Genetic Syndromes ◽

Medullary Thyroid ◽

High Penetrance ◽

Cowden’S Syndrome ◽

Small Increments

Familial non-medullary thyroid cancer (FNMTC) comprises about 5-15% of non-medullary thyroid cancer (NMTC) is a heterogeneous of diseases including both non-syndromic and syndrom forms , Non-syndromic FNMTC tends to manifest paillary thyroid carcinoma,usually multifocal and bilateral.Several high-penetrance genes for FNMTC have been indentified but they are often confined to a few or single families and other susceptibility loci appear to play a small part ,conferring only small increments in risk . Familial susceptibility is like to be due to a combination of genetic and environmental influences . The current focus of research in FNMTC is to charactetise the susceptibility genes and their role in carcinogenesis .FNMTC can also occur as a part of multitumor genetic syndromes such as familial adenomatous polyposis ,Cowden’s syndrome, Werner’s sydrome and Carney complex . There tend to present at an early age and are multicentric and bilateral with distinct pathology . The clinical evaluaion of these patients is similar to that for most patients with a thyroid nodule. Key words: Familial non-medullary thyroid cancer (FNMTC)

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Exceptionality of Distant Metastases in Node-Negative Hereditary and Sporadic Medullary Thyroid Cancer: Lessons Learned

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab214 ◽

2021 ◽

Author(s):

Andreas Machens ◽

Kerstin Lorenz ◽

Frank Weber ◽

Henning Dralle

Keyword(s):

Risk Factors ◽

Thyroid Cancer ◽

Lymph Node ◽

Medullary Thyroid Cancer ◽

Distant Metastases ◽

Node Negative ◽

Medullary Thyroid ◽

Primary Tumor Size ◽

Node Metastasis ◽

Node Positive

Abstract Context Risk factors of lymph node and distant metastases have rarely been analyzed in hereditary and sporadic medullary thyroid cancer (MTC) using large genetic-clinical data sets. Objective This comprehensive investigation aimed to explore risk factors of lymph node and distant metastases and interdependencies between age at thyroidectomy, primary tumor size, lymph node metastasis and distant metastasis in patients with hereditary and sporadic MTC. Methods Comparative analyses of risk factors of metastasis, stratified by hereditary MTC (four mutational risk categories) and sporadic MTC. Results There were 1115 patients with hereditary MTC (307 patients) or sporadic MTC (808 patients). Age at thyroidectomy increased proportionately from 12.2, 22.7, 34.3, and 49.8 years for patients with decreasing mutational risk, as compared to 52.1 years for patients with sporadic MTC. Metastatic primary tumors overall were 10.7–19.4 mm larger in node-positive patients and 15.9–19.3 mm larger in distant metastatic patients at thyroidectomy than nonmetastatic tumors. Distant metastases were noted in 13–50% of node-positive vs. 0% of node-negative hereditary MTC, and in 23.5% of node-positive vs. 1.7% of node-negative sporadic MTC. In multivariable logistic regression analysis for sporadic MTC, lymph node metastasis contributed to distant metastasis (odds ratio 12.4) more than primary tumor size (odds ratios of 7.8, 5.5 and 2.4 for tumors measuring >60, 41–60 and 21–40 mm). Conclusions When thyroidectomy is performed before lymph node metastases have developed, distant metastases are exceptional, both in patients with hereditary MTC, irrespective of the level of mutational risk, and patients with sporadic MTC.

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17 Thyroid diseasessurgical management ofcancer, medullarySurgical managementof thyroid diseasesthyroid cancer, medullaryMedullary thyroid cancers (MTCs)surgical management ofMedullary thyroid cancers (MTCs)Diseases, thyroidsurgical management ofcancer, medullaryCancersmedullary thyroid (MTCs)surgical management ofSurgical Management of Medullary Thyroid Cancer

Thyroid and Parathyroid Diseases ◽

10.1055/b-0036-141907 ◽

2016 ◽

Keyword(s):

Thyroid Cancer ◽

Surgical Management ◽

Medullary Thyroid Cancer ◽

Thyroid Cancers ◽

Medullary Thyroid

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A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer

Cancers ◽

10.3390/cancers12061441 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1441 ◽

Cited By ~ 2

Author(s):

Aayushi Srivastava ◽

Beiping Miao ◽

Diamanto Skopelitou ◽

Varun Kumar ◽

Abhishek Kumar ◽

...

Keyword(s):

Thyroid Cancer ◽

Germline Mutation ◽

Medullary Thyroid Cancer ◽

Current Knowledge ◽

Wild Type ◽

Medullary Thyroid ◽

Wild Type Counterpart ◽

In Silico Analyses ◽

Protection Of Telomeres 1

Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the Protection of Telomeres 1 (POT1) gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carrying POT1 p.V29L showed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation in POT1 has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers.

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Decreasing tumor size of thyroid cancer in Germany: institutional experience 1995–2009

Acta Endocrinologica ◽

10.1530/eje-10-0203 ◽

2010 ◽

Vol 163 (1) ◽

pp. 111-119 ◽

Cited By ~ 14

Author(s):

Andreas Machens ◽

Henning Dralle

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Tumor Size ◽

Medullary Thyroid Cancer ◽

Secular Trends ◽

Papillary Thyroid ◽

Follicular Thyroid Cancer ◽

Thyroid Cancers ◽

Medullary Thyroid ◽

Screening Programs

ObjectiveDecreasing tumor size in a population over time is widely interpreted as a measure of effectiveness of cancer screening programs. Nonetheless, thyroid cancer size is rarely analyzed as a function of time. This study aimed to explore secular trends of thyroid cancer diameter in Germany.DesignRetrospective analysis of 1644 thyroid cancer patients from a large referral center for thyroid cancer (1995–2009).MethodsCalculation of largest tumor diameters for each type of cancer as a function of time periods and birth cohorts.ResultsOver the past 25 years, subdivided into 5-year periods by year of thyroidectomy (1985–1989; 1990–1994; 1995–1999; 2000–2004; 2005–2009), tumor diameters diminished from 25 to 16 mm (P=0.025) for medullary thyroid cancer and from 28 to 18 mm (P=0.017) for papillary thyroid cancer. This reduction was greater for hereditary medullary thyroid cancer (from 27 to 11 mm; P=0.088) than sporadic medullary thyroid cancer (from 23 to 19 mm; P=0.11). No decline was observed for follicular thyroid cancer (means of 45 to 42 mm; P=0.52). From the first (1921–1940) to the most recent birth cohort (1981–2000), tumor size fell from 22 to 10 mm (P<0.001) for medullary thyroid cancer, from 24 to 22 mm (P<0.001) for papillary thyroid cancer, and from 49 to 38 mm (P=0.011) for follicular thyroid cancer. The reduction of medullary thyroid cancers affected exclusively patients with hereditary disease (from 20 to 7 mm; P<0.001).ConclusionThe consistency and robustness of these data signify powerful secular trends toward smaller papillary, follicular, and medullary thyroid cancers. The causes and consequences of these trends warrant further investigation.

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Risk factors of recurrent medullary thyroid cancer and factors that influence on prognosis

Journal of Clinical Oncology ◽

10.1200/jco.2005.23.16_suppl.5594 ◽

2005 ◽

Vol 23 (16_suppl) ◽

pp. 5594-5594

Author(s):

Y. H. Lee ◽

H. Y. Park ◽

J. H. Jung ◽

K. H. Hwang

Keyword(s):

Risk Factors ◽

Thyroid Cancer ◽

Medullary Thyroid Cancer ◽

Medullary Thyroid

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Medullary Thyroid Cancer: Case Series Reports and Literature Review

Journal of Cancer and Tumor International ◽

10.9734/jcti/2021/v11i430158 ◽

2021 ◽

pp. 29-37

Author(s):

Emad Rezkallah ◽

Andrew Elsaify ◽

Wael M. Elsaify

Keyword(s):

Overall Survival ◽

Thyroid Cancer ◽

Surgical Resection ◽

Medullary Thyroid Cancer ◽

Case Series ◽

Cervical Lymph Nodes ◽

Serum Calcitonin ◽

Thyroid Cancers ◽

Medullary Thyroid ◽

Regional Metastases

Background: Medullary thyroid carcinoma (MTC) is a rare neuro-endocrine tumor that arises from the C-cells of the thyroid. About 20- 25 % of MTC cases may be associated with hereditary syndromes like MEN 2A, MEN 2B and Familial MTC. The survival rate is related mainly to the age of the patient, stage of the disease and completion of the surgical resection. Methods: Retrospective review of 11 patients who were diagnosed with medullary thyroid cancer in our general surgery department during the period from 2011 to 2021. All patients had preoperative assessment including history taking, clinical examination, tumor marker (calcitonin and CEA), thyroid function testing, ultrasonography and FNAC. All patients underwent genetic assessment to exclude any underlying genetic mutation. Results: The mean age of diagnosis was 57.73 ± 16.45 years of age. Three patients were males and eight were females. All patients had total thyroidectomy, central and lateral neck dissection except one patient who had prophylactic thyroidectomy due to familial inherited RET mutation. Two patients had recurrence; both of them had high-stage tumor (T3 and T4) with multiple cervical lymph nodes metastasis. The sensitivity of serum calcitonin for the detection of MTC was about 98%. Patients, who had localized disease and underwent complete surgical resection, had good overall survival rates compared with patients with advanced disease. Conclusion: MTC represent a heterogeneous group of thyroid cancers. The overall survival is better than that of undifferentiated thyroid cancers. Complete resection of the thyroid tumor and any local or regional metastases provides the only cure for patients with MTC. Further researches are still needed to improve our understanding and management of MTC.

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