Open Access

The Landscape of Single Nucleotide Polymorphisms in Papillary Thyroid Carcinoma

KYRODIMOS EFTHYMIOS 1
CHRYSOVERGIS ARISTEIDIS 1
MASTRONIKOLIS NICHOLAS 2
PAPANASTASIOU GEORGE 3
TSIAMBAS EVANGELOS 4
SPYROPOULOU DESPOINA 5
KATSINIS SPYROS 6
MANOLI AREZINA 6
PAPOULIAKOS SOTIRIOS 7
PANTOS PAVLOS 1
RAGOS VASILEIOS 3
PESCHOS DIMITRIOS 8
  &  
PAPANIKOLAOU VASILEIOS 1

1First ENT Department, Hippocration Hospital, University of Athens, Athens, Greece

2ENT Department, Medical School, University of Patras, Patras, Greece

3Department of Maxillofacial, Medical School, University of Ioannina, Ioannina, Greece

4Department of Cytology, 417 Veterans Army Hospital (NIMTS), Athens, Greece

5Department of Radiation Oncology, Medical School, University of Patras, Patras, Greece

6Department of Otorhinolaryngology, Thoracic Diseases General Hospital Sotiria, Athens, Greece

7Department of Otolaryngology, GNA Hospital Gennimatas, Athens, Greece

8Department of Physiology, Medical School, University of Ioannina, Ioannina, Greece

Cancer Diagnosis & Prognosis Jan-Feb; 3(1): 26-30 DOI: 10.21873/cdp.10175
Received 12 August 2022 | Revised 21 July 2024 | Accepted 10 October 2022
Corresponding author
Evangelos Tsiambas, MD, MSc, Ph.D., Cytologist, 17 Patriarchou Grigoriou E΄ Street, Ag. Paraskevi, 153 41 Athens, Greece. E- tsiambasecyto@yahoo.gr

Abstract

Thyroid carcinoma represents a leading malignancy among those derived from human endocrine systems. It comprises a variety of different histological subtypes, including mainly papillary carcinoma, follicular carcinoma, anaplastic carcinoma, and medullar carcinoma. A broad spectrum of genetic imbalances, comprising gross chromosomal (polysomy/aneuploidy) and specific gene (mutations, amplifications, deletions) alterations, has been reported. Interestingly, the role of isolated, specific gene polymorphisms, especially of the single nucleotide polymorphism (SNP) type, in thyroid carcinoma is under investigation. SNPs are the most common genetic variations in the genome. The current molecular review focuses on the impact of specific SNPs on the biological behavior of papillary thyroid carcinoma in their carriers.
Keywords: Thyroid, carcinoma, DNA, gene, single nucleotide polymorphisms, review

Among endocrine malignancies, thyroid carcinoma is considered the most prominent and frequent (1,2). Although the exact etiology is under investigation, chronic exposure to ionizing radiation, environmental pollution substances, smoking, hormonal imbalances, and metabolic diseases (obesity) combined with sex (mainly females) have been implicated as critical factors for the onset and progression of the disease (3-5). Thyroid carcinoma demonstrates a variety of different histopathological subtypes, including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, anaplastic thyroid carcinoma, and medullar thyroid carcinoma (6-8). Concerning crucial genetic events detected in the corresponding epithelia, point mutations/amplification negatively affecting RAS proto-oncogene, GTPase/B-Raf proto-oncogene, serine/threonine kinase (BRAF) genes, and specific rearrangements in ret proto-oncogene (RET) lead to an overactivation of signal transduction pathways, such as RAS/RAF and mitogen-activated protein kinase, respectively (9-13). Epigenetic alterations, including DNA methylation, histone modifications (acetylation), micro-RNAs (miR) imbalances and chromatin re-organization, are also observed in thyroid carcinomas (14,15). Besides these genetic factors, specific micro-genetic signatures that occur familiarly or heritably (germline mutations) modify the genomic profile of future thyroid carcinoma patients (16,17). Specific nucleotide changes in different locations inside the genes can also be responsible for the overactivation or silencing of oncogenes and suppressor genes, respectively (18,19). In fact, single nucleotide polymorphisms (SNPs) are the most common genetic variations in the genome (20). All of these changes are considered potentially critical for thyroid carcinoma susceptibility and development (21). In the current review, we focus on the impact of specific SNPs detected in PTCs on the biological behavior of tumor in their carriers.

Gene Polymorphisms: Mechanisms and Categories

Since 2002, Human Genome Decoding Project revealed a broad spectrum of gene-based variants due to extended sequencing screening (22,23). In fact, DNA variants represent focal changes in the corresponding sequences by affecting their nucleotide composition or length (24,25). Concerning the molecular categorization of them under the term of DNA ‘’polymorphisms’’, variable number of tandem repeats (VNTRs), single nucleotide polymorphisms (SNPs), restriction fragment length polymorphism (RFLP), and simple tandem repeat (STRs) – microsatellites – have been recognized as prominent (26,27). The main mechanisms that create these polymorphisms include point mutations/substitutions, deletions and insertions, as well as base-pair multiple repeats (28). Genetic polymorphisms occur randomly across the whole genome at a percentage of at least 1% in the population. The majority are characterized as silent, having no effect on the functionality of the corresponding genes. However, critical nucleotide changes can drive the gene sequence to become a ‘malignant’ genotype, which leads to the formation of a neoplastic and finally cancerous cell phenotype due to not only a genomic, but also a transcriptomically altered substrate (29,30). They also lead to aberrant enzymatic activity and abnormal biochemical reactions in a variety of proteins that are involved in specific metabolic and signaling transduction pathways (31,32). In contrast to this, genetic polymorphisms enhance the diversity of a human population, which is a mechanism of biological evolution regarding all species in ecosystems (33).

SNPs in PTC

Extensive molecular, especially microgenetic, analyses have revealed a broad spectrum of SNPs in subgroups of patients diagnosed with thyroid carcinoma. Interestingly, specific SNPs characterize thyroid carcinomas of different histological subtypes, including mainly PTC, follicular carcinoma, anaplastic carcinoma, and medullar carcinoma (34). Implementing a high-resolution melting technique, one study group reported multiple detection of SNPs produced by inherent/germline or sporadic mutations in a series of PTC, correlating or not with the biological behavior of the malignancies in the patients (35). Similarly, another genetic study focused on the analysis of a specific population (Egyptians) in order to identify the potential impact of new SNPs on patients with PTC. In fact, they examined the role of SNPs of glucagon-like peptide-1 receptor (GLP1R) as a potential risk factor for carcinoma development. Based on a combination of immunohistochemistry and real-time polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), they observed that rs1042044 and rs6923761 SNPs in the GLP1R gene were most frequently detected in patients with PTC (36). Besides this, GLP1R overexpression correlated with lymph node metastasis and tumor stage was also associated with the presence of these SNPs. Another study group explored the role of the G allele of rs8101923 SNP in terminal differentiation-induced non-coding RNA genotyping of a series of PTCs by a PCR-RFLP protocol (37). They reported a higher risk of PTC in carriers of the rs8101923 G allele. Furthermore, another multi-SNP-based analysis in patients with PTC focused on the BTG anti-proliferation factor 3 (BTG3), caspase 9 (CASP9) and LDL-receptor related protein 4 (LRP4) genes. The study group observed that the concurrent presence of BTG3 rs9977638 CC, CASP9 rs884363 AC and LRP4 rs898604 AG SNPs significantly increased the risk of PTC susceptibility (38). In contrast, other detected SNPs, including the rs9977638 TC and CC, rs884363 CC and rs898604 GG genotypes, were not implicated in the carcinogenetic process. Another study group analyzed the role of SNPs detected in BCL3 transcription coactivator (BCL3), arachidonate 5-lipoxygenase-activating protein (ALOX5AP), and ferroptosis-related genes apolipoprotein E (APOE) genes (39). They genotyped a variety of polymorphisms including rs429358/rs7412 in APOE, rs34698726/8100239 in BCL3, and rs4076128/ rs4073259 in ALOX5AP, respectively. Among them, rs429358-TC, rs34698726-TA/TT, and rs8100239-AT/AA, respectively, were correlated with a high risk of developing PTC, whereas the other genotypes seemed to provide a level of protection in their carriers (normal-control group). Focused on a target population, another study examined the impact of a specific SNP (rs9939609) affecting fat mass and obesity-associated protein (FTO) gene on a PTC series in Iranian patients (40). They also explored the role of potential genetic variations in exon 3 of serpin family A member 5 (SERPINA5) gene. Based on a PCR-RFLP assay, they found that SERPINA5 rs6115G>A and rs6112T>C SNPs were potentially implicated in PTC onset, whereas FTO rs9939609 polymorphism was not associated with that risk.

Involvement of SNPs detected in apoptosis-related genes are also under investigation. Concerning the BCL2 apoptosis regulator-associated X, apoptosis regulator (BAX) gene, one study group reported a high prevalence in Brazilian patients with PTC due to a specific polymorphism (-248 G>A) that down-regulates BAX gene transcription leading to its reduced expression (41). Interestingly, the GG genotype seems to be a protective factor for the corresponding carriers. Similarly, analyzing SNPs in a Chinese population, Hao et al. focused on a specific gene, pecanex 2 (PCNXL2) (42). The study group considered the rs10910660 SNP in PCNXL2 to be a major microgenetic marker for increased PTC susceptibility. In contrast, another polymorphism (rs12129938) may potentially be a protective factor in the corresponding carriers. Analyzing the status of the X-ray repair cross-complementing group 1 (XRCC1) gene, which is implicated in DNA repair process, another study group reported a high prevalence of its Arg280His GA genotype in patients with differentiated PTCs (43). In contrast, PTC cases showed absence of the Arg280His AA genotype. Interestingly, the GA genotype was frequently identified in familial thyroid carcinoma cases. Analyzing specific short non-coding functional RNAs (miRNAs), Khan et al. focused on the role of miRNA-149-based SNPs and forkhead box E1 (FOXE1) gene (44). They concluded that SNP rs2292832 in miRNA-149 was associated with a high risk of PTC onset, whereas rs3758249 in FOXE1 demonstrated no correlation. Concerning new histotype variants of PTC, there is a specific SNP that is considered critical for its carriers. A molecular study applying PCR-RFLP in a series of micro-papillary PTCs reported that 1562C/T functional polymorphism is a crucial variant of matrix metalloproteinase-9 (MMP9) gene involved in this histological form of PTCs (45).

In conclusion, genetic polymorphisms occur randomly across the whole genome at a percentage of at least 1% in the human population overall. SNPs particularly implicated in thyroid carcinomas represent critical markers for identifying subgroups of patients based on molecular criteria. A broad spectrum of functional polymorphisms in a variety of genes affect their activity (overexpression in oncogenes/low expression in suppressors, respectively), driving normal epithelia to their neoplastic and progressively malignant phenotypes. Patients with PTC are carriers of many specific SNPs that modify the expression of the corresponding gene. Extensive SNP-based analyses in patients with PTC may provide useful molecular data for future targeted therapeutic approaches.

Conflicts of Interest

The Authors have no conflicts of interest to declare.

Authors’ Contributions

ET, AC, ET, and VP: Design of the study, article writing; NM, DP, VR, and DP: Academic advisors; SK, GP, AM, SP, and PP: Collection and management of references and published data. All Authors read and approved the final article.

References

1 Wang Z Luo J Zhang Y Xun P & Chen Z Metformin and thyroid carcinoma incidence and prognosis: A systematic review and meta-analysis. PLoS One. 17(7) e0271038 2022. PMID: 35901016. DOI: 10.1371/journal.pone.0271038
2 Graceffa G Salamone G Contino S Saputo F Corigliano A Melfa G Proclamà MP Richiusa P Mazzola S Tutino R Orlando G & Scerrino G Risk factors for anaplastic thyroid carcinoma: a case series from a tertiary referral center for thyroid surgery and literature analysis. Front Oncol. 12 948033 2022. PMID: 35875085. DOI: 10.3389/fonc.2022.948033
3 Canet M Harbron R Thierry-Chef I & Cardis E Cancer effects of low to moderate doses of ionizing radiation in young people with cancer-predisposing conditions: a systematic review. Cancer Epidemiol Biomarkers Prev. 31(10) 1871 - 1889 2022. PMID: 35861626. DOI: 10.1158/1055-9965.EPI-22-0393
4 Zamora-Ros R Cayssials V Clèries R Torrents M Byrnes G Weiderpass E Sandström M Almquist M Boutron-Ruault MC Tjønneland A Kyrø C Katzke VA Le Cornet C Masala G Krogh V Iannuzzo G Tumino R Milani L Skeie G Ubago-Guisado E Amiano P Chirlaque MD Ardanaz E Janzi S Eriksson L Freisling H Heath AK Rinaldi S & Agudo A Sweetened beverages are associated with a higher risk of differentiated thyroid cancer in the EPIC cohort: a dietary pattern approach. Eur J Nutr. PMID: 35907037. DOI: 10.1007/s00394-022-02953-5
5 Zamora-Ros R Cayssials V Franceschi S Kyrø C Weiderpass E Hennings J Sandström M Tjønneland A Olsen A Overvad K Boutron-Ruault MC Truong T Mancini FR Katzke V Kühn T Boeing H Trichopoulou A Karakatsani A Martimianaki G Palli D Krogh V Panico S Tumino R Sacerdote C Lasheras C Rodríguez-Barranco M Amiano P Colorado-Yohar SM Ardanaz E Almquist M Ericson U Bueno-de-Mesquita HB Vermeulen R Schmidt JA Byrnes G Scalbert A Agudo A & Rinaldi S Polyphenol intake and differentiated thyroid cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Int J Cancer. 146(7) 1841 - 1850 2020. PMID: 31342519. DOI: 10.1002/ijc.32589
6 Puliafito I Esposito F Prestifilippo A Marchisotta S Sciacca D Vitale MP & Giuffrida D Target therapy in thyroid cancer: current challenge in clinical use of tyrosine kinase inhibitors and management of side effects. Front Endocrinol (Lausanne). 13 860671 2022. PMID: 35872981. DOI: 10.3389/fendo.2022.860671
7 Jayasinghe R Basnayake O Jayarajah U & Seneviratne S Management of medullary carcinoma of the thyroid: a review. J Int Med Res. 50(7) 3000605221110698 2022. PMID: 35822284. DOI: 10.1177/03000605221110698
8 Lam AK & Lee KT Application of immunohistochemistry in papillary thyroid carcinoma. Methods Mol Biol. 2534 175 - 195 2022. PMID: 35670976. DOI: 10.1007/978-1-0716-2505-7_13
9 Ghosh C Kumar S Kushchayeva Y Gaskins K Boufraqech M Wei D Gara SK Zhang L Zhang YQ Shen M Mukherjee S & Kebebew E A Combinatorial strategy for targeting BRAFV600E-mutant cancers with BRAFV600E inhibitor (PLX4720) and tyrosine kinase inhibitor (Ponatinib). Clin Cancer Res. 26(8) 2022 - 2036 2020. PMID: 31937621. DOI: 10.1158/1078-0432.CCR-19-1606
10 Schulten HJ Salama S Al-Ahmadi A Al-Mansouri Z Mirza Z Al-Ghamdi K Al-Hamour OA Huwait E Gari M Al-Qahtani MH & Al-Maghrabi J Comprehensive survey of HRAS, KRAS, and NRAS mutations in proliferative thyroid lesions from an ethnically diverse population. Anticancer Res. 33(11) 4779 - 4784 2013. PMID: 24222113.
Pubmed |
11 Kim M Jeon MJ Oh HS Park S Kim TY Shong YK Kim WB Kim K Kim WG & Song DE BRAF and RAS mutational status in noninvasive follicular thyroid neoplasm with papillary-like nuclear features and invasive subtype of encapsulated follicular variant of papillary thyroid carcinoma in Korea. Thyroid. 28(4) 504 - 510 2018. PMID: 29439609. DOI: 10.1089/thy.2017.0382
12 Huang TS Lee JJ Huang SY & Cheng SP Regulation of expression of sterol regulatory element-binding protein 1 in thyroid cancer cells. Anticancer Res. 42(5) 2487 - 2493 2022. PMID: 35489723. DOI: 10.21873/anticanres.15727
13 Song YS Won JK Yoo SK Jung KC Kim MJ Kim SJ Cho SW Lee KE Yi KH Seo JS & Park YJ Comprehensive transcriptomic and genomic profiling of subtypes of follicular variant of papillary thyroid carcinoma. Thyroid. 28(11) 1468 - 1478 2018. PMID: 30226444. DOI: 10.1089/thy.2018.0198
14 Lee EK Chung KW Yang SK Park MJ Min HS Kim SW & Kang HS DNA methylation of MAPK signal-inhibiting genes in papillary thyroid carcinoma. Anticancer Res. 33(11) 4833 - 4839 2013. PMID: 24222120.
Pubmed |
15 Forte S La Rosa C Pecce V Rosignolo F & Memeo L The role of microRNAs in thyroid carcinomas. Anticancer Res. 35(4) 2037 - 2047 2015. PMID: 25862858.
Pubmed |
16 Verrienti A Carbone A Sponziello M Pecce V Cito DS & Bruno R Papillary thyroid carcinoma as first and isolated neoplastic disease in a Lynch syndrome family member with a germline MLH1 mutation. Endocrine. 77(1) 199 - 202 2022. PMID: 35415788. DOI: 10.1007/s12020-022-03048-1
17 Sánchez-Ares M Cameselle-García S Abdulkader-Nallib I Rodríguez-Carnero G Beiras-Sarasquete C Puñal-Rodríguez JA & Cameselle-Teijeiro JM Susceptibility genes and chromosomal regions associated with non-syndromic familial non-medullary thyroid carcinoma: some pathogenetic and diagnostic keys. Front Endocrinol (Lausanne). 13 829103 2022. PMID: 35295987. DOI: 10.3389/fendo.2022.829103
18 Albertson DG Collins C McCormick F & Gray JW Chromosome aberrations in solid tumors. Nat Genet. 34(4) 369 - 376 2003. PMID: 12923544. DOI: 10.1038/ng1215
19 Hanahan D & Weinberg RA Hallmarks of cancer: the next generation. Cell. 144(5) 646 - 674 2011. PMID: 21376230. DOI: 10.1016/j.cell.2011.02.013
20 Stratton MR Campbell PJ & Futreal PA The cancer genome. Nature. 458(7239) 719 - 724 2009. PMID: 19360079. DOI: 10.1038/nature07943
21 Kaubryte J & Lai AG Pan-cancer prognostic genetic mutations and clinicopathological factors associated with survival outcomes: a systematic review. NPJ Precis Oncol. 6(1) 27 2022. PMID: 35444210. DOI: 10.1038/s41698-022-00269-5
22 Collins A Mapping in the sequencing era. Hum Hered. 50(1) 76 - 84 2000. PMID: 10545760. DOI: 10.1159/000022893
23 Wheeler DL Chappey C Lash AE Leipe DD Madden TL Schuler GD Tatusova TA & Rapp BA Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 28(1) 10 - 14 2000. PMID: 10592169. DOI: 10.1093/nar/28.1.10
24 Smigielski EM Sirotkin K Ward M & Sherry ST dbSNP: a database of single nucleotide polymorphisms. Nucleic Acids Res. 28(1) 352 - 355 2000. PMID: 10592272. DOI: 10.1093/nar/28.1.352
25 Sherry ST Ward M & Sirotkin K Use of molecular variation in the NCBI dbSNP database. Hum Mutat. 15(1) 68 - 75 2000. PMID: 10612825. DOI: 10.1002/(SICI)1098-1004(200001)15:1<68::AID-HUMU14>3.0.CO;2-6
26 Koike A Nishida N Inoue I Tsuji S & Tokunaga K Genome-wide association database developed in the Japanese Integrated Database Project. J Hum Genet. 54(9) 543 - 546 2009. PMID: 19629137. DOI: 10.1038/jhg.2009.68
27 Sherry ST Ward MH Kholodov M Baker J Phan L Smigielski EM & Sirotkin K dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 29(1) 308 - 311 2001. PMID: 11125122. DOI: 10.1093/nar/29.1.308
28 Almomani R van der Heijden J Ariyurek Y Lai Y Bakker E van Galen M Breuning MH & den Dunnen JT Experiences with array-based sequence capture; toward clinical applications. Eur J Hum Genet. 19(1) 50 - 55 2011. PMID: 21102627. DOI: 10.1038/ejhg.2010.145
29 Lence-Anta JJ Xhaard C Ortiz RM Kassim H Pereda CM Turcios S Velasco M Chappe M Infante I Bustillo M García A Clero E Maillard S Salazar S Rodriguez R & de Vathaire F Environmental, lifestyle, and anthropometric risk factors for differentiated thyroid cancer in cuba: a case-control study. Eur Thyroid J. 3(3) 189 - 196 2014. PMID: 25538901. DOI: 10.1159/000362928
30 Lim LM Chung WY Hwang DY Yu CC Ke HL Liang PI Lin TW Cheng SM Huang AM & Kuo HT Whole-exome sequencing identified mutational profiles of urothelial carcinoma post kidney transplantation. J Transl Med. 20(1) 324 2022. PMID: 35864526. DOI: 10.1186/s12967-022-03522-4
31 Fessart D Villamor I Chevet E Delom F & Robert J Integrative analysis of genomic and transcriptomic alterations of AGR2 and AGR3 in cancer. Open Biol. 12(7) 220068 2022. PMID: 35857928. DOI: 10.1098/rsob.220068
32 Rehman K Jabeen K Awan FR Hussain M Saddique MA & Akash MSH Biochemical investigation of rs1801282 variations in PPAR-γ gene and its correlation with risk factors of diabetes mellitus in coronary artery disease. Clin Exp Pharmacol Physiol. 47(9) 1517 - 1529 2020. PMID: 32416637. DOI: 10.1111/1440-1681.13339
33 Almigbal TH Batais MA Hasanato RM Alharbi FK Khan IA & Alharbi KK Role of Apolipoprotein E gene polymorphism in the risk of familial hypercholesterolemia: a case-control study. Acta Biochim Pol. 65(3) 415 - 420 2018. PMID: 30235358. DOI: 10.18388/abp.2017_2344
34 Vollger MR Guitart X Dishuck PC Mercuri L Harvey WT Gershman A Diekhans M Sulovari A Munson KM Lewis AP Hoekzema K Porubsky D Li R Nurk S Koren S Miga KH Phillippy AM Timp W Ventura M & Eichler EE Segmental duplications and their variation in a complete human genome. Science. 376(6588) eabj6965 2022. PMID: 35357917. DOI: 10.1126/science.abj6965
35 Smith RA & Lam AK Single nucleotide polymorphisms in papillary thyroid carcinoma: clinical significance and detection by high-resolution melting. Methods Mol Biol. 2534 149 - 159 2022. PMID: 35670974. DOI: 10.1007/978-1-0716-2505-7_11
36 Abdul-Maksoud RS Elsayed WSH Rashad NM Elsayed RS Elshorbagy S & Hamed MG GLP-1R polymorphism (rs1042044) and expression are associated with the risk of papillary thyroid cancer among the Egyptian population. Gene. 834 146597 2022. PMID: 35598685. DOI: 10.1016/j.gene.2022.146597
37 Wang Q Huang H Chen P Xiao X Luo X Wang Y Long S Gao L & Zhang L Genetic predisposition to papillary thyroid carcinoma is mediated by a long non-coding RNA TINCR enhancer polymorphism. Int Immunopharmacol. 109 108796 2022. PMID: 35489191. DOI: 10.1016/j.intimp.2022.108796
38 Zhang F Fan G & Wang X Correlation between BTG3, CASP9 and LRP4 single-nucleotide polymorphisms and susceptibility to papillary thyroid carcinoma. Biomark Med. 16(7) 537 - 547 2022. PMID: 35362324. DOI: 10.2217/bmm-2021-0711
39 Xiao Z & Zhao H Ferroptosis-related APOE, BCL3 and ALOX5AP gene polymorphisms are associated with the risk of thyroid cancer. Pharmgenomics Pers Med. 15 157 - 165 2022. PMID: 35241926. DOI: 10.2147/PGPM.S352225
40 Moshtaghioun SM Fazel-Yazdi N Mandegari M Shirinzadeh-Dastgiri A Vakili M & Fazel-Yazdi H Evaluation the presence of SERPINA5 (Exon 3) and FTO rs9939609 polymorphisms in papillary thyroid cancer patients. Asian Pac J Cancer Prev. 22(11) 3641 - 3646 2021. PMID: 34837923. DOI: 10.31557/APJCP.2021.22.11.3641
41 Cardoso-Duarte LCA Fratelli CF Pereira ASR Souza JNG Freitas RS Morais RM Sobrinho AB Sousa Silva CM de Oliveira JR Oliveira DM & Silva ICR BAX gene (-248 G>A) polymorphism in a sample of patients diagnosed with thyroid cancer in the Federal District, Brazil. Int J Biol Markers. 36(4) 21 - 26 2021. PMID: 34825595. DOI: 10.1177/17246008211057576
42 Hao R Han P Zhang L Bi Y Yan J Li H Bai Y Xu C Li B & Li H Genetic polymorphisms in the PCNXL2 gene are risk factors for thyroid cancer in the Chinese population. Future Oncol. 17(34) 4677 - 4686 2021. PMID: 34747634. DOI: 10.2217/fon-2021-0748
43 Kirnap NG Tutuncu NB Yalcin Y Cebi H Tutuncu T Nar A Verdi H & Atac FB GA genotype of the Arg280His polymorphism on The XRCC1 gene: Genetic susceptibility genotype in differentiated thyroid carcinomas. Balkan J Med Genet. 24(1) 73 - 80 2021. PMID: 34447662. DOI: 10.2478/bjmg-2021-0003
44 Khan R Shaheen H Mansoor Q Abbasi SA Fatima S Ammar A & Baig RM Genetic predisposition of SNPs in miRNA-149 (rs2292832) and FOXE1 (rs3758249) in thyroid Cancer. Mol Biol Rep. 48(12) 7801 - 7809 2021. PMID: 34643920. DOI: 10.1007/s11033-021-06795-y
45 Dobrescu R Schipor S Manda D Caragheorgheopol A & Badiu C Matrix metalloproteinase-9 (MMP-9) promoter -1562C/T functional polymorphism is associated with an increased risk to develop micropapillary thyroid carcinoma. Cancer Biomark. 34(4) 555 - 562 2022. PMID: 35275517. DOI: 10.3233/CBM-203119