Genetic variants and risk of thyroid cancer among Iranian patients
Article in Hormone Molecular Biology and Clinical Investigation · February 2021
DOI: 10.1515/hmbci-2020-0051
CITATIONS
0
READS
27 6 authors, including:
Some of the authors of this publication are also working on these related projects:
Inhibition of MicroRNA miR-222 with LNA Inhibitor Can Reduce Cell Proliferation in B Chronic Lymphoblastic LeukemiaView project
Investigation of IL28B gene rs12979860 polymorphism in the HCV patients and healthy population in Tehran Province, IranView project Mohammad Jamshidi
Lorestan University of Medical Sciences 15PUBLICATIONS 122CITATIONS
SEE PROFILE
Gholamreza Farnoosh
Baqiyatallah University of Medical Sciences 55PUBLICATIONS 604CITATIONS
SEE PROFILE
Fatemeh Rafiee
8PUBLICATIONS 36CITATIONS SEE PROFILE
Ali Saeedi-Boroujeni
Ahvaz Jundishapur University of Medical Sciences 24PUBLICATIONS 165CITATIONS
SEE PROFILE
All content following this page was uploaded by Ali Saeedi-Boroujeni on 28 August 2021.
The user has requested enhancement of the downloaded file.
Review Article
Mohammad Jamshidi, Gholamreza Farnoosh, Somayeh Mohammadi Pour, Fatemeh Ra fi ee, Ali Saeedi Boroujeni and Mohammad-Reza Mahmoudian-Sani*
Genetic variants and risk of thyroid cancer among Iranian patients
https://doi.org/10.1515/hmbci-2020-0051 Received July 24, 2020; accepted January 14, 2021;
published online February 8, 2021
Abstract: The definition of an exclusive panel of genetic markers is of high importance to initially detect among this review population. Therefore, we gave a summary of each main genetic marker among Iranian patients with thyroid cancer for the first time which were classified based on their cellular function. Due to the results, a significant relationship was found between SNP in codons 194, 280, and 399 (XRCC1), Allele 3434Thr (XRCC7), GC or CC geno- type 31, G/C (Survivin), 399G>A (XRCC1),Tru9I (vitamin D receptor), G‐D haplotype (MDM2), TT genotype,−656 G/T (IL-18), TAGTT haplotype (IL-18), G allele in +49 A>G (CTLA-4),+7146 G/A (PD-1.3),+7785 C/T (PD-1.5), rs1143770 (let7a‐2), rs4938723 (pri‐mir‐34b/c) genes, and thyroid cancers. Moreover, SNP in 677C–>T (MTHFR), GG genotype Asp1312Gly (thyroglobulin), 2259C>T (Rad52), R188H, (XRCC2), T241M (XRCC3) had higher risks of thyroid cancer and lower risks were observed in −16 Ins-Pro (p53), rs3742330 (DICER1). At last, the protective effects were explored in 127 CC genotype (IL-18), rs6877842 (DROSHA).
Conduct further studies on the types of DNA repair gene polymorphisms with a larger number in the thyroid cancer using modern methods such as SNP array so that these genes could be used as a biomarker in prediction, diag- nosis, and treatment of thyroid cancer. This review pre- sents for the first time a summary of important genetic markers in Iranian patients with thyroid cancer.
Keywords:biomarker; genotyping; Iran; single nucleotide polymorphisms; thyroid cancer.
Introduction
The study indicated that thyroid cancer is one of the most common and important endocrine malignancies [1] ac- counting 1–2% of all types of cancer [2]. The thyroid cancer occurrence has increased more rapidly than any other malignancy, and an increased incidence was reported in both genders and all races [3]. However, an increased incidence is somewhat caused by the earlier diagnosis of the disease. Thyroid cancer is more common in females than in males [4, 5]. Thyroid cancer results from follicular or parafollicular cells of thyroid, and there arefive types of thyroid cancer. Differentiated thyroid cancer (DTC) in- cludes the most thyroid cancers. The source of these can- cers is follicular cells in the thyroid. Moreover, about nine out of 10 cases of thyroid cancer are papillary carcinomas.
Follicular carcinoma, also known as follicular cancer, is the second most common type of thyroid cancer which involves about one out of 10 cases of thyroid cancer. These cancers are more common in the countries where people do not take enough iodine from their diet. Besides, medullary thyroid carcinoma (MTC) leads to around 1% of thyroid cancers that result from C cells in thyroid gland. Anaplastic carcinoma which is also known as non-differentiated car- cinoma, is a rare form of thyroid cancer and accounts for approximately 1% of all thyroid cancers. Another cancer is thyroid lymphoma which is very rare in thyroid gland.
Lymphomas are cancers resulting from lymphocytes which are the main type of immune cells. A thyroid sarcoma is
*Corresponding author: Mohammad-Reza Mahmoudian-Sani, Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, Phone:+98 061 33750410, Fax:+98 061 33750427, E-mail: [email protected]
Mohammad Jamshidi,Department of Laboratory Sciences, School of Allied Medicine, Lorestan University of Medical Sciences,
Khorramabad, Iran
Gholamreza Farnoosh,Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran Somayeh Mohammadi Pour,Department of Obstetrics and Gynecology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
Fatemeh Rafiee,Cancer Gene Therapy Research Center, Zanjan University of Medical Science, Zanjan, Iran
Ali Saeedi Boroujeni,Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran;
ImmunologyToday, Universal Scientific Education and Research Network (USERN), Tehran, Iran
other rare cancer beginning in the thyroid supporting cells is often invasive and difficult to treat [6, 7]. Radiation, ge- netic factors, underlying thyroid disease, hormonal factors (that is more prevalent in females), and nutritional factors, in particular, iodine, play vital roles in the pathogenesis of thyroid cancer [7, 8]. Due to the results of ATA study in 2104 and other research, including Oberman et al.’s study [9], factors like diabetes mellitus, obesity, age, female gender, height, weight, and body mass index (BMI), exposure to ionized radiation, pregnancy, and lifestyle and climate changes can affect the disease incidence [10, 11]. Moreover, some studies referred to the relationship between family history of thyroid cancer, obesity, and TSH with thyroid cancer [12–14]. Besides, one of the studies performed dur- ing 2001–2005 reported a significant increase in thyroid cancer in Iran [15]. The studies have shown that thyroid cancer incidence increased by 14.3 cases per 100,000 people in the United States in 2009 which is almost three times the rate reported in 1975 (4.9 per 100,000 people]
[16]. Furthermore, American Cancer Society reported a diagnosis of 62,980 new thyroid cancer cases by 2014 so that most of the diagnosed and new cases were female and people under the age of 65. Besides, it occurs significantly among Asians, and its incidence is two times more com- mon in the white than in the black [8, 16–18]. As stated by Larijani et al. in National Cancer Registry System in Iran during 1996–2000, the incidence rate of thyroid cancer in males and females is 3.5 and 1%, respectively. Single nucleotide polymorphisms (SNP) which determine the phenotype among individuals as the genetic variation contributes to susceptibility to cancers and development of disease [19]. However, the risk level evaluation is one of the most important parameters to choose individuals to perform prevention and screening processes. There are commercially available diagnostic tests in the field of screening which will predict the risk of cancer in each individual corresponding to the population by identifying common risk alleles in population. These tests were established using population confirmation of poly- morphisms identified by genome-wide association studies (GWAS) and other candidate gene studies [19]. The identi- fied polymorphisms include single-nucleotide and multi- nucleotide changes, deletions, and additions. SNPs are the simplest and most common changes in the human genome from among these changes, accounting for about 90% of polymorphisms. Notably, less than 1% of all SNPs are located in protein-coding regions. This fact indicates the probable relationship between the presence of a small part of these SPNs and phenotypic changes. One of the most important objectives of genetic studies is to identify SNPs which alleles related to diseases and are recognized as the
susceptible factors to disease in different individuals. It is noteworthy that in this research, a summary of important genetic markers for thefirst time in Iranian patients with thyroid cancer is given (Table 1). Consequently, genetic markers listed are grouped into distinct cellular approaches due to their respective cellular functions (Figure 1).
Vitamin D
It is widely accepted that the active form of vitamin D leads to inhibit the proliferative effect of the thyroid-stimulating hormone (TSH) on thyroid cells by binding to its receptor in collaboration with genomic and non-genomic mecha- nisms; therefore, vitamin D can play a significant role to regulate the proliferation of thyroid gland [20]. In fact, binding the active form of vitamin D to its receptor has many pleiotropic effects including regulating calcium and phosphate metabolism, cell division, differentiation, apoptosis, angiogenesis, and cell metastasis. Hence, cal- citriol can be a very important factor in anticancer re- sponses [21]. Several studies confirmed the anticancer effects of vitamin D in prostate, breast, and colon cancers and endocrine tumors. The inhibition of cell proliferation and induction of cell differentiation accompanied by the induction of apoptosis and inhibition of angiogenesis are considered the major anticancer parameters of vitamin D [21, 22]. However, multiple polymorphisms were identified in different introns and exons of the receptor gene of vitamin D includingTrn9I andBsmI in intron 8,FokI in exon 2, andTaqI in exon 9, each of which make changes in the protein function with expression of vitamin D receptor [23–25]. One of the studies evaluated receptor poly- morphisms of vitamin D in patients with follicular and papillary thyroid cancers and indicated a significant rela- tionship between Apa I and FokI polymorphisms and follicular cancer. Moreover, Taq I and Bsm I poly- morphisms showed no significant relationship in either of the two types of thyroid cancer [26]. In another similar study on Iranian population with follicular and papillary thyroid cancers, the results did not reveal any significant relationship betweenTru9I,TaqI,ApaI, andBsmI poly- morphisms; however, there was a significant difference in Tru9I polymorphism allelic frequency between the patient and control groups [27].
Plasminogen activating system
There is numerous experimental evidence that the plas- minogen activating system is involved in the destruction of
Table:Typesofthestudies’markersinTCsusceptibilityamongtheIranianpatients. SNP/GenePopulationTypeTechniquesResultsRef Intron(GC)/Ppatients controlsTCa PCR-RFLPb NoimportantassociationbetweenPintron(GC) polymorphismandriskofdevelopmentofTC[] IntronInsbpandexon ArgPro/ppatients controlsTCAS-PCRc Therewasassociationbetween(−ins-Pro)haplotypewith reducedriskofdifferentiatedTCdevelopment[] ArgTrp,ArgHisArgGln/ XRCCpatients controls DTCdPCR-RFLP PCR-HRMeGenotypingofcodons,,andinXRCCgenemight useinriskassessmentofDTC[] C–>T/MTHFRpatients controls
DTCMultiplexPCRMTHFRC–>Thomozygousvariantallelemaybeassociated totheincreasedriskofDTC[] AlleleThr/XRCCpatients controls DTCARMSf-PCRAlleleThrinXRCCgenemightbeassociatedtothe differentiatedTCrisk.[] −(G/C)(rs)/Survivinpatients controls
PTCgPCR-RFLPFrequencyofGCorCCgenotypeinpatientswithPTCwas meaningfullyhigherthaninthecontrols[] rs/estrogenreceptorbetapatients controlsTCARMS-PCRNosignificantassociationbetweenrspolymorphism andnodularthyroiddisease[] Codon/ppatients controlsTCDNAsequencing SSCPh ARMS Polymorphismatcodonpgeneisnotageneticpredis- posingfactorforTC[] rsSNP/XRCCpatients controls
DTCPCR-RFLPNoimportantdifferencesingenotypesbetweencaseandcon- trolgroups[] G/G/PAI-patients controlsTCARMS-PCRGenotypicandallelicfrequenciesofPAI-G/Gpolymorphism exhibitednoimportantdifferencebetweenTCandcontrol[] AspGly(rs)/ thyroglobulinpatients controlsDTCHRMRecessiveGGgenotypewasassociatedtoanincreasedriskof DTC[] C>TandG>A/XRCCpatients controlsDTCPCR-RFLPXRCCG>Agenotypemightbeusedasavaluablemolecular biomarkertopredictgeneticsusceptibilityforDTC[] FokI,BsmIandTruI/vitaminD receptorpatients controlsMTCi PCR-sequencingGenotypicandallelicabundanceofFokIandBsmIpoly- morphismsbetweentestandcontrolgroupshavenotshown importantdifferent.TruIpolymorphismissignificantlylinked toMTCprevalence
[] rsA>C/MDMpatients controls
TCTetra-ARMSPCRLackofanyobservedassociationbetweenMDMrs polymorphismandTC[] T>G(rs) I/D(rs)/MDMpatients controls PTCPCR-RFLPG‐DhaplotypebutnotMDMT>GandI/Dpolymorphisms wererelatedtohigherriskofPTC.MDMT>Gpolymorphism wasassociatedtoahigherincidenceofIII–IVsteps,however, I/Dpolymorphismwasassociatedwithlargertumorsizeanda lowerageofdiseaseoccurrence
[] −G/T(rs) −C/A(rs) G/C(rs) T/G(rs) C/T(rs)inIL-gene
patients controls TCPCR–RFLP ASPCR IncreasedsusceptibilitytoTCinsubjectswithTTgenotypeat position−G/TofpromoterofIL-gene,aswellasTAGTT haplotypeoccurredfromfivestudyingSNPsinIL-gene. CCgenotypemightprotectindividualsfromTCderivedfrom follicularepithelium
[]
Table:(continued) SNP/GenePopulationTypeTechniquesResultsRef −C>T +A>GintheCTLA-patients controlsTC(papillary,follic- ular,andanaplastic).ARMS-PCRandRFLP-PCRGallelein+A>Gandpossiblylowerexpressionofmutated CTLA-molecule,isassociatedtothehighersusceptibilitytoTC. ThepresenceofAalleleseemedtoincreasetheoddsforPTCin patientswithHashimoto’sdisease
[] (G>C)Rad(C>T)Rad (RH)XRCC(TM)XRCCpatients controlsDTCPCR-HRMCombinedvariantformofRad,XRCC,XRCCexposedan elevatedriskofDTC.ItissuggestedthatRadC>T,XRCC RHandXRCCTMpolymorphismsshouldbesimulta- neouslyconsideredascontributingtoapolygenicriskofDTC [] +G/A(PD-.) +C/T(PD-.)patients controlsTCPCR–RFLPTheassociationofPD-.C/Tpolymorphismandahaplotype resultedfrombothloci,PD-.andPD-.,withsusceptibility ofIranianstoTC
[] (rs)leta‐ (rs)pri‐mir‐b/cpatients controlsPTCPCR–RFLPleta‐rsandpri‐mir‐b/c rspolymorphismswererelatedwithahigherriskof PTC [] (rs)DICER,(rs) DROSHA (rs)XPO
patients controls PTCPCR-RFLPDICERrspolymorphismwasrelatedwithlowerriskof PTC.DROSHArspolymorphismcouldbeaprotective factorfortumorgrowthinPTCpatients
[] C/T(rs)+A/G (rs)CTLA-patients controlsHTj ARMSNoimportantdifferenceswereobservedingenotypeandallele frequenciesinSNPsbetweencasesandcontrols[] AC(rs) AC(rs) TPO
patients controls HypothyroidismPCR-RFLPEvaluatinggenepolymorphismsofTPOexonandthemea- surementofanti-TPOantibodieslevelsislikelytobehelpfulin patientswithsubclinicalhypothyroidism
[] FokIandApaIvitaminDreceptorpatients controlsAITDsk PCR-RFLPFokIpolymorphismsareinvolvedinAITDssusceptibilityinIran northwestpopulation[] a ThyroidCancer.b polymerasechainreaction–restrictionfragmentlengthpolymorphism.c Allele-specificpolymerasechainreaction.d Differentiatedthyroidcancer.e polymerasechainreactionhigh resolutionmelting.famplification-refractorymutationsystem.gPapillarythyroidcarcinoma.hsscpsinglestrandconformationpolymorphism.iMedullaryThyroidCancer.jHashimotoThyroiditis. kAutoimmunethyroiddiseases.DTC,differentiatedthyroidcancer;MTC,medullarythyroidcarcinoma.
basement membrane and extracellular matrix and results in the invasion of tumor cells and metastases [28]. This system contains TPA tissue plasminogen activator, UPAR urokinase receptor, UPA urokinase plasminogen activator, andPAI-1 andPAI-2 plasminogen activator inhibitors [29].
PAI-1 gene is one of the main inhibitors offibrin degrada- tion by inactivating the tissue and urokinase plasminogen activators which also contributes to the regulation of cell migration, cell adhesion, and invasion [30]. The human PAI-1 gene is placed on the long arm of chromosome 7 with nine exons and eight introns synthesized in the vascular endothelium and its production is regulated by hormones, cytokines, and growth factors [31]. AmongPAI-1 gene var- iants, 4G/5G polymorphism was studied more than others.
This polymorphism is located in gene promoter region, which shows its possible contribution to transcriptional regulation [32, 33]. Carriers of 4G/4G genotype have higher PAI-1 concentrations than 5G/5G genotype because both alleles can bind to the transcription activator, whereas the 5G allele binds to a repressor protein and reduces tran- scription ofPAI-1 gene.
Steroids
Epidemiologic findings and empirical evidence about thyroid lesions indicate that female sex hormones, espe- cially estrogen, may affect this gland and its neoplasms. In fact, benign and malignant thyroid lesions are more com- mon in females, and their prognosis is better in females [34]. Thyroid diseases occur in many women of reproduc- tive age when the concentration of estrogen and proges- terone hormones reaches its peak levels. In most cases, follicular adenomas and well-differentiated carcinomas occur in women that are more common in post- adolescence and pre-menopausal years [35]. The inci- dence rate of thyroid carcinoma in women of reproductive age is about three times higher than in men [36]. The expression level of alpha estrogen receptor is higher in
patients with different types of thyroid neoplasms than in normal people; however, the expression level of beta es- trogen receptor in different types of thyroid neoplasms is lower than in normal people [37]. Estrogen receptors and thyroid hormone are superfamily members of nuclear re- ceptors [38]. The estrogen receptor is located in cytoplasm and nucleus. Therefore, when estrogen enters the cell and binds to estrogen receptors, the receptor can directly affect DNA transcription. Due to the prevalence of thyroid nod- ules among women and the proof of the dependence of thyroid cancer on estrogen as the main female hormone, it is necessary to further examine estrogen and its receptor. In fact, if there is a relationship between phenotype and ge- notype in the receptor mutations of estrogen beta and different types of thyroid nodules, more appropriate diag- nosis and therapeutic solutions will be considered by the physician for each patient. The prevalence of benign and malignant thyroid diseases in women has encouraged many researchers to study the role of sex hormones in thyroid diseases [39].
Apoptosis and cell cycle
Thep53gene is one of the most important suppressor genes involved in cancer. This gene is located on the short arm of chromosome 17 which has 11 exons of 5 kb in length [40]. In addition to mutation, another cause of the cancer inci- dence is genetic polymorphisms. Polymorphism refers to the presence of allelic differences in a gene locus which is a factor responsible for individual differences in unique traits and susceptibility to disease, the frequency of cancer in a population, the age of cancer incidence in an indi- vidual, or response to cancer treatment, as well as inter- action with known mutations susceptible to disease [41].
Moreover, ethnic and geographical variations are involved in the function of the p53gene polymorphisms. Thep53 polymorphisms were found in both coding and non-coding regions so that at least two polymorphisms were
Figure 1:All the cellular pathway which are involved in TC progression among Iranian patients.
discovered among which only two polymorphisms alter the amino acid sequence of thep53protein. One of them is the alteration of proline to serine at codon 47, and the other is proline to arginine alteration at codon 72. This poly- morphism is more common and encodes three Arg/Arg homozygote, Arg/pro heterozygote, and or pro/pro ho- mozygote genotypes [42]. Research indicated this poly- morphism is related to an increased risk of many cancers including lung, nasopharyngeal, oral, prostate, and colo- rectal cancers, and may also be considered a thyroid marker cancer. Boltz et al. (2002) examined Caucasian patients and showed that homozygote proline at codon 72 of thep53gene could be a risk factor to develop undiffer- entiated thyroid carcinoma [43]. Moreover, Granja et al.
(2004) conducted a study in Brazil and indicated a signif- icant relationship between pro/pro variant and suscepti- bility to thyroid cancer [44]. Besides, Aral et al. (2007) examined patients in Turkey and revealed a significant relationship between homozygote proline at codon 72 and thyroid cancer development in Turkish patients [45].
Finally, researchers in Brazil (2010) showed a relationship between polymorphism at codon 72 of thep53gene and thyroid cancer so that the heterozygous pro/Arg genotype increased about 3.5 times the risk of thyroid nodule malignancy compared to other genotypes [46].
Due to the analyses, homozygosity for the proline allele increased susceptibility to develop thyroid cancer in Turkish and Brazilian patients [46, 47]. However, due to Boltz et al., there was no relationship between the geno- types of codon 72 and differentiated thyroid cancer in German patients, though there is a relationship between proline homozygote genotype and poor prognosis as well as the greater risks of progressing non-differentiated car- cinoma [44]. Studies showed that double mouse minute 2 homolog (MDM2) which is one of the main negative regu- lators of the tumor suppression pathways ofp53, functions by directly binding to the p53 gene and causes ubiq- uitinylation and degradation of thep53gene [48]. More- over, Mdm4 p53 binding protein homolog (MDM4) that has homology with MDM2 in terms of structure can collaborate with MDM2 to inhibitp53activities while responding the cell to the DNA damages [49]. Besides, researchers showed that rs4245739 A>C SNP in 3′-untranslated region (3′-UTR) of MDM4 is a putative targeted site for miR-191 [50]. In fact, miR-191 is able to selectively attach to the C allele con- sisting of MDM4 mRNA but not A allele containing MDM4 mRNA and thus this situation causes a decreased expres- sion of C allele containing MDM4 mRNA. Such a condition refers to higher expression of MDM4 mRNA and protein in MDM4 rs4245739 A allele carrier in the occurred malig- nancies [51]. Furthermore, dysfunctions in the p53
pathways contribute significantly to the mammary tumorgenesis. Regarding the contribution of p53-MDM4 pathways to the prevention of the tumor progression, re- searchers hypothesized that rs4245739 A>C polymorphism of MDM4 could play a role in the TC pathogenesis. How- ever, documents indicated the amplification of murine double minute 2 (MDM2) gene and abnormal level of MDM2 proteins in various tumors [52, 53]. Notably, MDM2 is a major modulator of the cell cycle by inactivating and degrading p53 protein. Studies showed that MDM2 would present multiple p53‐independent functions in transcribing, regulating cell-cycle, differentiating, or syn- thesizing DNA [54]. Finally, researchers found two func- tionalMDM2 285G>C (rs117039649) and 309T>G (rs2279744) polymorphisms into the intronic promoter region (P2) with 24‐base‐pair distance. Moreover, there was a relationship between MDM2 rs2279744 and rs937283 polymorphisms with the differentiated thyroid carcinomas [55].
Survivin
Survivin is a new member of proteins family inhibiting programmed cell death. This molecule is abundantly expressed in embryonic tissues, its expression in normal adult tissues is insignificant which could not be traced [56].
Moreover, survivin expression is also highly specific to the tumor which introduced as the fourth transcriptomic expressing in tumor cells [57]. However, the expression of Survivin and its binding in cancer cells and its differences from natural types have led to using this molecule as a major diagnostic marker in cancer [58]. Molecular studies indicated that a decrease in survivin expression in thyroid cancer cells would increase apoptosis and susceptibility to the chemotherapeutic agents [59]. Moreover, the increased expression of survivin is related to invasion, metastasis, and tumor development [60–62].
DNA repair
XRCC4 is one of the genes involved in non-homologous end joining (NHEJ) system. The protein obtained from this gene contributes to DNA double-strand break repair by helping protein product of genes such as Ku70/Ku80, XLF, and ligase 4, so that XRCC7 binds to it after breaking the binding of Ku70/Ku80 to the two ends of DNA and providing a suitable substrate. Then,XRCC4, along with ligase4, binds to it and connects two broken strands of DNA [63]. In fact, KUheterodimeris a sensor that detects DNA damages by binding to broken ends, holds two ends of
DNA together by forming a scaffold, and allows DNA-PKCS to act on them. In such a condition, DNA-PKCS transforms into a functional protein and binds the phosphate groups to several acceptor proteins to accomplish other steps. In fact,XRCC4 gene acts as a tumor suppressor with a role to preserve chromosome stability [64]. However, one of the studies conducted in Saudi Arabia addressed the rela- tionship between DNA repair genes polymorphisms, includingXRCC4, and papillary cancer development and showed that there is only a relationship between RAD52 GLN221GLU and papillary thyroid cancer; however, there was no significant relationship between G>4ARCA poly- morphism and thyroid cancer [65]. In another study in Portugal (2010), researchers examined 109 patients and 217 controls and confirmed that there was a relationship be- tween NHEJ gene polymorphism and thyroid cancer in which a direct relationship was observed between Ku80 and thyroid cancer so that people with T 18,067 poly- morphism were more likely to be affected by DTC [66].
Besides, one of the case-control studies showed that the greater risks for DTC were recognized with XRCC1 Arg194Trp [67] and XRCC1 Arg399Gln genotypes [68].
Moreover, Zhu QX et al. indicated that 194 C>T poly- morphism had no significant relationship with thyroid cancer regarding this polymorphism [68]. Contrarily, re- searchers found that there is a relationship between 194C>T variant homozygote genotype and the greater risks of DTC [69]; however, it has a relationship with lower risks of DTC in a Korean population [70].
Immune response
Due to the research, interleukin-18 (IL-18) is one of the proinflammatory cytokines and a member of IL-1 super- family generated by diverse cells, in particular, kupffer cells of liver and actuated macrophages [71]. Moreover, research showed that the thyroid cells generate IL-18 in responding to the TSH in a dosage-dependent way [72].
Besides, studies showed that intrathyroidal collaboration of IL-18 with IFNγinvolves in degeneration of the thyroid tissues in Hashimoto’s thyroiditis [73]. In fact, the human IL-18 gene hasfive common SNPs, three of them are located in the promoter region (−656 G/T,−607 C/A,−137 G/C), and two of them are located in thefive-untranslated region (UTR) (+113 T/G,+127 C/T) [74, 75]. Therefore, researchers suggested interference of−607 C/A and−137 G/C SNPs in the promoter region with the transcription factors (TFs)- binding sites [75]. Furthermore, the above two SNPs related to susceptibility to colorectal, stomach, lung, and breast cancers in the Iranian population [76–78]. Cytotoxic
T lymphocyte antigen 4 (CTLA-4 or CD152) is found among these molecules and thus its presence on actuated T-cells would act as an “off-switch”to control immune system [79]. In fact, irregular expression of CTLA-4 gene in the people with the environmental and genetic predisposition for cancer and or autoimmune diseases can enhance the risks of initiating and progressing the disease [80]. How- ever, regarding the contribution of SNPs to the expression ofCTLA-4 gene [81] and possible functions of protein [82], it could be assumed that such SNPs contribute to initiating and developing the autoimmune and neoplastic illnesses [80]. Experts in the field determined above 100 SNPs in CTLA-4 gene, and a majority of SNPs had relationships with diverse susceptibility to illnesses like auto-immune lympho-proliferative syndrome, insulin-dependent dia- betes mellitus, celiac disease, systemic lupus erythemato- sus, and Hashimoto thyroiditis. Besides, the alterations of CTLA-4 gene contribute to multiple human neoplasms like the breast, gastro-intestinal, cervix, lung, and squamous cell carcinomas and leukemia’s and lymphomas [80]. In this regard, Chang et al. [83] indicated that the distribution of AA genotype and allele frequency of +49 A>G were highly declined in patients with thyroid carcinoma. Also, there is a relationship between AA genotype and more acceptable responses to the radioidoine-131 treatment. It is widely accepted that the programmed cell death (PD-1) and the respective cognate ligands (PD-L1 and PD-L2) are the co-inhibitory molecules of the human immune system, restraining the rapid growth and actuation of B and T lymphocytes to preserve peripheral tolerance [84]. In fact, researchers confirmed the coinfiltration of PD-1+ T lym- phocytes and Foxp3-positive regulatory T (Treg) cells in the tumor-induced lymph node of papillary cancer [85].
Therefore, researchers suggested that such a condition had a relationship with an undesirable prognosis in patients [85]. In fact, PD-1 is ideally overexpressed on the T regs and enhances inhibitory function by intra-cellular modulation of Foxp3. Then, variations in PD-1and Foxp3 genes can affect risks of the progression of colon cancer as well as metastasis risks in colorectal cancer [86, 87].
Noncoding RNAs and epigenetic modification
The studies indicated that polymorphisms might cause atypical miRNA expression and thus influence the expres- sion of the targeted genes in the microRNA machinery genes. Hence, they can be risk factors for dysfunctions or disorders such as tumors [88]. Besides, researchers
published a decrease of DICER1 mRNA expression in the thyroid cancer. Therefore, the deterioration of miRNA pro- cessing such as DICER possibly involves developing thyroid cancer [89]. Since the transporter XPO5 plays a role in miRNA synthesis pathways, expressing miRNA can be influenced by structural alterations in XPO5 gene, which probably causes the tumor progression [90]. In this regard, Wen et al. confirmed the relationship between XPO5 rs11077 polymorphism and TC initiation. Moreover, detection of the decreased level of XPO5 expression has been observed in the G allele patients [91]. Multiple investigations examined the effects of DROSHA polymorphisms on cancer risks. Due to the performed research, Let7a‐2 is one of the miRNAs belonging to the let-7 family. It suppresses the rapid growth, invasion, migration, and tumor development in cancer [92].
Multiple investigations observed a relationship between cancer and let7a‐2 polymorphisms [93, 94]. Moreover, some studies reported a relationship between miR‐34b/c as one of the members of miR‐34 family and various cancers [95, 96].
Nonetheless, scarce reports have dealt with probable im- pacts of pri‐mir‐34b/c and let7a‐2 polymorphisms on the thyroid cancer [94, 97]. In this regard, Wang et al. showed a possible relationship between let7a‐2 rs10877887 poly- morphism and the declined risks of PTC and a relationship between rs13293512 polymorphism and the lymph node metastasis in the PTC patients [94]. Finally, Chen et al. re- ported the relationship of pri‐mir‐34b/c rs4938723 TC, CC, and TC+CC genotypes with the enhanced risk of PTC in China [97].
Conclusions
This review provided a summary of each important genetic marker among Iranian TC patients for the first time.
Apparently, apoptosis, cell cycle, DNA repair, noncoding RNA, epigenetic modification, immune responses, cell signaling, and steroid metabolism are the cell and molec- ular procedures that have been frequently published and play a role to develop tumor among Iranian patients with thyroid cancer. Based on Table 1, the presence of SNP in intron 6 G13964C (TP53), rs1256049 (estrogen receptor beta), codon 72 (p53), rs1805377 (XRCC4), 4G/5G (PAI-1), FokI,BsmI (vitamin D receptor), rs4245739 A>C (MDM4), rs2279744, rs3730485 (MDM2), 318C/T (rs5742909) (CTLA-4), and+49A/G (rs231775) (CTLA-4) genes has no significant relationship with any types of thyroid cancer, while there is a significant relationship between SNP in codons 194, 280, and 399 (XRCC1), allele 3434Thr (XRCC7), GC or CC genotype 31, G/C (Survivin), 399G>A (XRCC1), Tru9I (vitamin D receptor), G‐D haplotype (MDM2), TT
genotype, −656 G/T (IL-18), TAGTT haplotype (IL-18), G allele in+49 A>G (CTLA-4),+7146 G/A (PD-1.3),+7785 C/T (PD-1.5), and rs1143770 (let7a‐2), rs4938723 (pri‐mir‐34b/c) genes and thyroid cancers. Moreover, research indicated that SNP in 677C–>T (MTHFR), GG genotype Asp1312Gly (thyroglobulin), 2259C>T (Rad52), R188H, (XRCC2), T241M (XRCC3) has a greater risk of thyroid cancers and thus lower risk was observed in−16 Ins-Pro (p53), rs3742330 (DICER1).
Finally, the protective effect was explored in 127 CC geno- type (IL-18), rs6877842 (DROSHA). Therefore, it could be concluded that this study would have advantages for developing the population-based diagnostic panel markers to detect thyroid cancer among the Iranian people initially.
Besides, the study clarified the genetic and molecular foundations of the development in the mentioned popu- lation. However, various investigations dealt with the relationship among SNPs and greater risks of distinct kinds of TCs in diverse Iranian populations. Regarding the prominent and fundamental role of DNA repair genes in thyroid cancer, it is suggested to conduct further studies on types of DNA repair gene polymorphisms with a larger number in the thyroid cancer using modern methods such as SNP array so that these genes could be used as a biomarker in prediction, diagnosis, and treatment of thy- roid cancer.
Research funding:This study was not funded by anyone.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests:The authors declare that they have no competing interests.
Informed consent:Not applicable.
Ethical approval:This article does not contain any studies with human participants or animals performed by any of the authors.
Availability of data and materials:The datasets used and/
or analyzed during the current study are available from the corresponding author on reasonable request.
References
1. Deandrea M, Gallone G, Veglio M, Balsamo A, Grassi A, Sapelli S, et al. Thyroid cancer histotype changes as observed in a major general hospital in a 21-year period. J Endocrinol Invest 1997;20:
52–8.
2. Feldt-Rasmussen U. Iodine and cancer. Thyroid 2001;11:483–6.
3. Kohler BA, Ward E, McCarthy BJ, Schymura MJ, Ries LA, Eheman C, et al. Annual report to the nation on the status of cancer, 1975–2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst 2011;103:714–36.
4. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA A Cancer J Clin 2011;61:69–90.
5. Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988–2005. Cancer:
Interdiscipl Int J Am Cancer Soc 2009;115:3801–7.
6. Segev DL, Umbricht C, Zeiger MA. Molecular pathogenesis of thyroid cancer. Surg Oncol 2003;12:69–90.
7. Torlontano M, Attard M, Crocetti U, Tumino S, Bruno R, Costante G, et al. Follow-up of low risk patients with papillary thyroid cancer: role of neck ultrasonography in detecting lymph node metastases. J Clin Endocrinol Metabol 2004;89:3402–7.
8. Xu L, Port M, Landi S, Gemignani F, Cipollini M, Elisei R, et al.
Obesity and the risk of papillary thyroid cancer: a pooled analysis of three case–control studies. Thyroid: Off J Am Thyroid Assoc 2014;24:966–74. .
9. Oberman B, Khaku A, Camacho F, Goldenberg D. Relationship between obesity, diabetes and the risk of thyroid cancer. Am J Otolaryngol 2015;36:535–41.
10. Bann DV, Goyal N, Camacho F, Goldenberg D. Increasing incidence of thyroid cancer in the Commonwealth of Pennsylvania. JAMA Otolaryngol Head Neck Surg 2014;140:
1149–56.
11. Lehrer S, Rosenzweig KE. Cold climate is a risk factor for thyroid cancer. Clin Thyroidol 2014;26:273–6.
12. Memon A, De Gonzalez AB, Luqmani Y, Suresh A. Family history of benign thyroid disease and cancer and risk of thyroid cancer. Eur J Canc 2004;40:754–60.
13. Ma J, Huang M, Wang L, Ye W, Tong Y, Wang H. Obesity and risk of thyroid cancer: evidence from a meta-analysis of 21
observational studies. Med Sci Mon Int Med J Exp Clin Res 2015;
21:283.
14. Hong K-S, Son J-W, Ryu OH, Choi M-G, Hong JY, Lee SJ. Cardiac effects of thyrotropin oversuppression with levothyroxine in young women with differentiated thyroid cancer. Int J Endocrinol 2016;2016:6.
15. Khayamzadeh M, Khayamzadeh M, Tadayon N, Salmanian R, Zham H, Razzaghi Z, et al. Survival of thyroid cancer and social determinants in Iran. Asian Pac J Cancer Prev 2011;12:95–8.
16. Karkoobi Y, Moradi G, SharifiP, Ghafoori S. Assessment of thyroid cancer risk factors in Kurdistan province. Sci J Kurdistan Univ Med Sci 2018;23:10–8.
17. Morris LG, Myssiorek D. Improved detection does not fully explain the rising incidence of well-differentiated thyroid cancer:
a population-based analysis. Am J Surg 2010;200:454–61.
18. Davies L, Welch HG. Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg 2014;140:317–22.
19. Erichsen HC, Chanock SJ. SNPs in cancer research and treatment.
Br J Canc 2004;90:747–51.
20. Mehta RG, Mehta RR. Vitamin D and cancer. J Nutr Biochem 2002;
13:252–64.
21. Ordonez-Moran P, Larriba MJ, Pendas-Franco N, Aguilera O, Gonzalez-Sancho JM, Munoz A. Vitamin D and cancer: an update of in vitro and in vivo data. Front Biosci 2005;10:2723–49.
22. Slattery ML. Vitamin D receptor gene (VDR) associations with cancer. Nutr Rev 2007;65:S102–S4.
23. Hutchinson PE, Osborne JE, Lear JT, Smith AG, Bowers PW, Morris PN, et al. Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma. Clin Canc Res 2000;6:498–504.
24. Ntais C, Polycarpou A, Ioannidis JPA. Vitamin D receptor gene polymorphisms and risk of prostate cancer: a meta-analysis.
Cancer Epidemiol Biomark Prev 2003;12:1395–402.
25. Ye WZ, Reis AF, Velho G. Identification of a novel Tru9 I polymorphism in the human vitamin D receptor gene. J Hum Genet 2000;45:56–7.
26. Penna-Martinez M, Ramos-Lopez E, Stern J, Hinsch N, Hansmann M-L, Selkinski I, et al. Vitamin D receptor polymorphisms in differentiated thyroid carcinoma. Thyroid: Off J Am Thyroid Assoc 2009;19:623–8.
27. Haghpanah V, Ghaffari SH, Rahimpour P, Abbasi A, Saeedi M, Pak H, et al. Vitamin D receptor gene polymorphisms in patients with thyroid cancer. Gene Ther Mol Biol B 2007;11:299–304.
28. Horvatic Herceg G, Herceg D, Kralik M, Kulic A, Bence-Zigman Z, Tomic-Brzac H, et al. Urokinase plasminogen activator and its inhibitor type-1 as prognostic factors in differentiated thyroid carcinoma patients. Otolaryngology-Head Neck Surg (Tokyo) 2013;149:533–40.
29. Ulisse S, Baldini E, Sorrenti S, Barollo S, Gnessi L, Catania A, et al.
High expression of the urokinase plasminogen activator and its cognate receptor associates with advanced stages and reduced disease-free interval in papillary thyroid carcinoma. J Clin Endocrinol Metabol 2011;96:504–8.
30. Mashiko S, Kitatani K, Toyoshima M, Ichimura A, Dan T, Usui T, et al. Inhibition of plasminogen activator inhibitor-1 is a potential therapeutic strategy in ovarian cancer. Canc Biol Ther 2015;16:
253–60.
31. Torres-Carrillo N, Magdalena Torres-Carrillo N, Vázquez- Del Mercado M, Rangel-Villalobos H, Parra-Rojas I, Sánchez- Enríquez S, et al. Distribution of–844 G/A and Hind III C/G PAI-1 polymorphisms and plasma PAI-1 levels in Mexican subjects:
comparison of frequencies between populations. Clin Appl Thromb Hemost 2008;14:220–6.
32. Palmirotta R, Ferroni P, Savonarola A, Martini F, Ciatti F, Laudisi A, et al. Prognostic value of pre-surgical plasma PAI-1 (plasminogen activator inhibitor-1) levels in breast cancer. Thromb Res 2009;
124:403–8.
33. Zhang H, Dong P, Yang X, Liu Z. Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with coronary artery disease risk: a meta-analysis. Int J Clin Exp Med 2014;7:3777–88.
34. Lewy-Trenda I. Estrogen and progesterone receptors in neoplastic and non-neoplastic thyroid lesions. Pol J Pathol 2002;
53:67–72.
35. Money SR, Muss W, Thelmo WL, Boeckl O, Pimpl W, Kaindl H, et al.
Immunocytochemical localization of estrogen and progesterone receptors in human thyroid. Surgery 1989;106:975–9.
36. Mazzaferri EL, Young RL, Oertel JE, Kemmerer WT, Page CP.
Papillary thyroid carcinoma: the impact of therapy in 576 patients. Medicine (Baltim) 1977;56:171–96.
37. Liu J, Chen G, Meng X-Y, Liu Z-H, Dong S. Serum levels of sex hormones and expression of their receptors in thyroid tissue in female patients with various types of thyroid neoplasms. Pathol Res Pract 2014;210:830–5.
38. Vasudevan N, Ogawa S, Pfaff D. Estrogen and thyroid hormone receptor interactions: physiologicalflexibility by molecular specificity. Physiol Rev 2002;82:923–44.
39. Shick PC, Riordan GP, Foss RD. Estrogen and progesterone receptors in salivary gland adenoid cystic carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;80:440–4.
