NOP53 as A Candidate Modifier Locus for Familial Non-Medullary Thyroid Cancer

Nonsyndromic familial non-medullary thyroid cancer (FNMTC) represents 3–9% of thyroid cancers, but the susceptibility gene(s) remain unknown. We designed this multicenter study to analyze families with nonsyndromic FNMTC and identify candidate susceptibility genes. We performed exome sequencing of DNA from four affected individuals from one kindred, with five cases of nonsyndromic FNMTC. Single Nucleotide Variants, and insertions and deletions that segregated with all the affected members, were analyzed by Sanger sequencing in 44 additional families with FNMTC (37 with two affected members, and seven with three or more affected members), as well as in an independent control group of 100 subjects. We identified the germline variant p. Asp31His in NOP53 gene (rs78530808, MAF 1.8%) present in all affected members in three families with nonsyndromic FNMTC, and not present in unaffected spouses. Our functional studies of NOP53 in thyroid cancer cell lines showed an oncogenic function. Immunohistochemistry exhibited increased NOP53 protein expression in tumor samples from affected family members, compared with normal adjacent thyroid tissue. Given the relatively high frequency of the variant in the general population, these findings suggest that instead of a causative gene, NOP53 is likely a low-penetrant gene implicated in FNMTC, possibly a modifier.

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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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Functional consequences of germline mutations in a novel non-RET medullary thyroid cancer susceptibility gene

Endocrine Abstracts ◽

10.1530/endoabs.38.oc5.1 ◽

2015 ◽

Author(s):

Martin Read ◽

Joel Smith ◽

Vicki Smith ◽

Emy Bosseboeuf ◽

Naomi Wake ◽

...

Keyword(s):

Thyroid Cancer ◽

Medullary Thyroid Cancer ◽

Cancer Susceptibility ◽

Susceptibility Gene ◽

Germline Mutations ◽

Medullary Thyroid ◽

Functional Consequences ◽

Cancer Susceptibility Gene

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Evidence that polymorphisms in detoxification genes modulate the susceptibility for sporadic medullary thyroid carcinoma

Acta Endocrinologica ◽

10.1530/eje-11-0843 ◽

2012 ◽

Vol 166 (2) ◽

pp. 241-245 ◽

Cited By ~ 15

Author(s):

R B Barbieri ◽

N E Bufalo ◽

R Secolin ◽

A C N Silva ◽

L V M Assumpção ◽

...

Keyword(s):

Regression Analysis ◽

Thyroid Cancer ◽

Stepwise Regression ◽

Differentiated Thyroid Cancer ◽

Medullary Thyroid Cancer ◽

Cell Cycle Control ◽

Control Group ◽

Healthy Individuals ◽

Medullary Thyroid ◽

Low Penetrance Genes

AimPolymorphic low-penetrance genes have been consistently associated with the susceptibility to a series of human tumors, including differentiated thyroid cancer.MethodsTo determine their role in medullary thyroid cancer (MTC), we used TaqMan SNP method to genotype 47 sporadic MTC (s-MTC) and a control group of 578 healthy individuals for CYP1A2*F, CYP1A1m1, GSTP1, NAT2 and 72TP53. A logistic regression analysis showed that NAT2C/C (OR=3.87; 95% CI=2.11–7.10; P=2.2×10−5) and TP53C/C genotypes (OR=3.87; 95% CI=1.78–6.10; P=2.8×10−4) inheritance increased the risk of s-MTC. A stepwise regression analysis indicated that TP53C/C genotype contributes with 8.07% of the s-MTC risk.ResultsWe were unable to identify any relationship between NAT2 and TP53 polymorphisms suggesting they are independent factors of risk to s-MTC. In addition, there was no association between the investigated genes and clinical or pathological features of aggressiveness of the tumors or the outcome of MTC patients.ConclusionIn conclusion, we demonstrated that detoxification genes and apoptotic and cell cycle control genes are involved in the susceptibility of s-MTC and may modulate the susceptibility to the disease.

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Calcitonin negative medullary thyroid cancer in ectopic thyroid tissue: a rare diagnosis in an unusual location

BMJ Case Reports ◽

10.1136/bcr-2020-236865 ◽

2020 ◽

Vol 13 (8) ◽

pp. e236865

Author(s):

Gareth Montgomery ◽

Laurence Collins ◽

Caroline Coghlin ◽

Ramzan Ullah

Keyword(s):

Thyroid Cancer ◽

Disease Surveillance ◽

Medullary Thyroid Cancer ◽

Thyroid Tissue ◽

Immunohistochemical Analysis ◽

Disease Recurrence ◽

Care Physician ◽

Ectopic Thyroid ◽

Medullary Thyroid ◽

Ectopic Thyroid Tissue

Medullary thyroid cancer is an aggressive form of thyroid cancer arising from parafollicular C cells. Calcitonin (CT) is a specific and sensitive biochemical marker which typically aids primary diagnosis and disease surveillance following treatment. There are rare cases of calcitonin negative medullary thyroid cancer (CNMTC) documented in the literature; however, to our knowledge, this case is the first report of CNMTC arising in ectopic thyroid tissue. We report a case of a 45-year-old man who attended his primary care physician with painless anterior neck swelling. In the absence of CT secreting disease, we have demonstrated the investigative process and the importance of immunohistochemical analysis to achieve a diagnosis. We also consider the challenges of monitoring disease recurrence in the absence of reliable biochemical markers.

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Identification of SPRY4 as a novel candidate susceptibility gene for familial non-medullary thyroid cancer

Thyroid ◽

10.1089/thy.2020.0290 ◽

2021 ◽

Author(s):

Inês J. Marques ◽

Inês Gomes ◽

Marta Pojo ◽

Carolina Pires ◽

Margarida M. Moura ◽

...

Keyword(s):

Thyroid Cancer ◽

Medullary Thyroid Cancer ◽

Susceptibility Gene ◽

Medullary Thyroid

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SERUM LEVEL OF DIPEPTIDYL PEPTIDASE-4 AS A POTENTIAL BIOMARKER FOR MEDULLARY THYROID CANCER

Experimental Oncology ◽

10.31768/2312-8852.2018.40(4):299-302 ◽

2018 ◽

Vol 40 (4) ◽

pp. 299-302

Author(s):

R Abooshahab ◽

E Niyazi ◽

P Yaghmaie ◽

H G Ghadaksaz ◽

M Hedayati

Keyword(s):

Insulin Resistance ◽

Thyroid Cancer ◽

Medullary Thyroid Cancer ◽

Serum Levels ◽

Dipeptidyl Peptidase ◽

Control Group ◽

Medullary Thyroid ◽

Dipeptidyl Peptidase 4 ◽

Potential Biomarker ◽

Significant Difference

Aim: Adipokines are the proteins secreted from adipose tissue and play an important role in the control of metabolism. Dipeptidyl peptidase-4 (DPP4) is a novel adipokine with different biological role. As indicated by various studies, serum levels of DPP4 had been associated with body mass index (BMI), insulin resistance, metabolic syndrome and malignancy. The aim of this study was to assess the serum levels of DPP4 in patients with medullary thyroid cancer (MTC) in comparison with these in the control group. Materials and Methods: This study was performed on 45 MTC patients (24 females and 21 males) and 45 healthy controls (21 females and 24 males). DPP4 and insulin serum levels were measured by ELISA, fasting glucose serum levels by enzymecalorimetric method and insulin resistance index (HOMA-IR) by calculation using relevant equation. BMI (kg/m2) was also calculated. Results: Our data did not demonstrate a significant difference between serum DPP4 levels in MTC and healthy group (41.06 ± 22.08 ng/ml vs 39.94 ± 20.77 ng/ml, p > 0.05). Additionally, no significant difference was found in serum insulin and HOMA-IR concentrations between MTC patients and the controls (p > 0.05). Conclusions: This study suggests that the fluctuation in the levels of DPP4 does not play an important role in prognosis, early detection and diagnosis of MTC. Furthermore, higher levels of DPP4 cannot be considered as a risk factor for MTC.

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Elevated level of serum carbohydrate antigen 19.9 as predictor of mortality in patients with advanced medullary thyroid cancer

Acta Endocrinologica ◽

10.1530/eje-15-0304 ◽

2015 ◽

Vol 173 (3) ◽

pp. 297-304 ◽

Cited By ~ 11

Author(s):

Rossella Elisei ◽

Loredana Lorusso ◽

Paolo Piaggi ◽

Liborio Torregrossa ◽

Giovanni Pellegrini ◽

...

Keyword(s):

Thyroid Cancer ◽

Elevated Level ◽

Medullary Thyroid Cancer ◽

Rapid Evolution ◽

Carbohydrate Antigen ◽

Control Group ◽

Medullary Thyroid ◽

Risk Of Mortality ◽

Ca 19.9 ◽

Serum Carbohydrate Antigen

BackgroundMedullary thyroid cancer (MTC) is capable of secreting several proteins, such as calcitonin (Ct), carcinoembryonic antigen (CEA), chromogranin and others. Recently, we observed an aggressive MTC with high levels of serum carbohydrate antigen 19.9 (Ca 19.9) and a rapid evolution to death.ObjectiveThe aim of this study was to evaluate whether high levels of serum Ca 19.9 could be a prognostic factor of death in patients with advanced MTC.Patients and methodsWe measured Ca 19.9, CEA and Ct in 100 advanced structural recurrent/persistent MTC patients and in 100 cured or biochemically affected MTC patients. Clinical and pathological data were also collected.ResultsSixteen percent of the patients with advanced MTC had high levels of Ca 19.9. The group with abnormal Ca 19.9 levels had significantly higher levels of CEA and Ct compared with the group with normal values of Ca 19.9 (P<0.0001 for both Ct and CEA). At variance, all 100 patients in the MTC control group showed normal levels of Ca 19.9. Moreover, among the advanced cases, the Ca 19.9-positive group showed a higher mortality rate than the group with normal levels. A logistic regression analysis demonstrated that an elevated level of Ca 19.9 is a predictor of mortality (OR=3.78,P=0.04), independent from Ct doubling time.ConclusionsThese results demonstrated that an elevated value of serum Ca 19.9 appears to be a predictive factor of poor prognosis in advanced MTC patients and identifies those cases with a higher risk of mortality in the short term.

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Medullary thyroid cancer is associated with high serum vitamin D level and polymorphism of vitamin D receptors

Physiology International ◽

10.1556/2060.2020.00011 ◽

2020 ◽

Vol 107 (1) ◽

pp. 120-133

Author(s):

M Ramezani ◽

M Mazani ◽

M Tabatabaei ◽

A Rahimian ◽

E Mosaferi ◽

...

Keyword(s):

Vitamin D ◽

Thyroid Cancer ◽

Medullary Thyroid Cancer ◽

Serum Vitamin ◽

Test Group ◽

Allelic Frequency ◽

Control Group ◽

Medullary Thyroid ◽

Vitamin D Receptors ◽

Serum Vitamin D

AbstractBackgroundThyroid cancer is the most common endocrine malignancy. Studies have observed an anti-cancer effect for vitamin D and found that polymorphisms of vitamin D receptors can influence the prevalence of various cancers. The present study investigated the serum level of vitamin D and FokI, BsmI and Tru9I polymorphisms of vitamin D receptors.MethodsForty patients with medullary thyroid cancer and 40 healthy controls were investigated. The genomic DNA of the subjects was extracted using saturated salt/proteinase K and investigated by PCR sequencing. Serum levels of vitamin D were evaluated by ELISA. The results were analyzed in SPSS and GraphPad Prism 5 software.ResultsThe genotypic and allelic frequencies of FokI and BsmI polymorphisms showed no significant differences between test and control groups. For Tru9I polymorphism, Tt genotype and t allelic frequency in the test group were significantly different from those of the control group. Also, we found Tt genotype and t allelic frequency to be significantly associated with medullary thyroid cancer (MTC) type and the agressiveness of the disease. The average serum vitamin D level was 23.32 ng/mL and 18.95 ng/mL for patients and controls, respectively, and the difference between the two groups was statistically significant. Moreover, we found high serum vitamin D level to be associated with t allelic frequency.ConclusionsUnexpectedly, the mean serum vitamin D level of the test group was significantly higher than that of the control group. Tru9I polymorphism was found to be significantly correlated with the prevalence of medullary thyroid carcinoma.

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