| In the endocrine system, thyroid carcinoma(TC) is a very common malignant tumor. It occurs more often in young adults. In the majority, the pathological type is papillary thyroid carcinoma(PTC). 40-60 years is the incidence peak of TC. Male to female ratio is approaching 1:3. In recent years, the incidence of thyroid cancer has a rising tendency. The pathogenesis of thyroid cancer does not have a clear result. With the improvements in molecular biology techniques, some molecular markers which are associated with TC have been confirmed. MAPK pathway is a kind of serine/threonine protein kinase, communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell through conservative three-level cascade(MAPKKK-MAPKK-MAPK) activation of transcription factors, regulating gene expression. This pathway is associated with a variety of cellular functions, can be involved in cell movement, apoptosis, differentiation and proliferation of a variety of physiological processes. Among them, the KRAS, NRAS, HRAS, ALK, MET and VEGFA genes play an important role in the MAPK pathway.ObjectiveOur study aims to explore the association of gene polymorphism in the MAPK pathway with papillary thyroid cancer and provide some evidence for the etiology research of thyroid cancer.MethodsWe selected a case-control design. In case group, 860 papillary thyroid cancer patients(PTC group) and 420 nodular goiter patients(NG group) were recruited. In normal control group(NC group), 896 healthy individuals free of thyroid diseases were recruited. Age and gender were matched with cases in the control subjects. By using Clot Blood DNA Kit, Genomic DNA from peripheral blood lymphocytes of each case was extracted. By using an i PLEX Gold reagent set, the SNPs’ Genetic polymorphisms were genotyped. By using self-designed questionnaire, demographic and clinical data of all cases were collected. In data entry, Epidata3.1 was used. Instatistical analysis, SPSS19.0, SNPStats, Haploview4.2 and UNPHASE were used.Results1. Totally 13 tag SNPs on KRAS, HRAS, NRAS, ALK, MET and VEGFA were screened using soft Haploview 4.2 in Hap Map and NCBI-db SNP database. They were rs712, rs7315339 and rs12427141 on KRAS, rs12628 on HRAS, rs2273267 and rs14804 on NRAS, rs1881421 on ALK, rs1621 and rs6566 on MET, rs3024997,rs3025040, rs25648 and rs10434 on VEGFA.2. In accordance with H-W equilibrium(P>0.05), rs12628, rs2273267, rs14804,rs1621, rs6566, rs3025040, rs25648 and rs10434, the above 8 tag SNPs frequency and correlation analysis could be performed. Hardy-Weinberg equilibrium showed that rs7315339 in PTC, rs712, rs12427141 and rs1881421 in NC, rs3024997 in NG&NC were not according.3. The following genotypes were associated with PTC(P<0.05): GA genotype of rs1621 in MET gene(ORGA/AA=1.346, 95%CI=1.064-1.703), GG genotype of rs6566 in MET gene(ORGG/AA=1.391, 95%CI=1.063-1.822), GT genotype of rs712 in KRAS gene(ORGT/GG=1.334, 95%CI=1.084-1.641), AA genotype of rs12427141 in KRAS gene(ORAA/GG=3.685, 95%CI=1.352-10.047). The following genotypes were associated with gender disparity in PTC(P<0.05): GT genotype of rs712 in KRAS gene(ORGT/GG=1.436, 95%CI=1.132-1.821), AA genotype of rs12427141 in KRAS gene(ORAA/GG=3.280, 95%CI=1.183-9.095), GC genotype of rs1881421 in ALK gene(ORGC/GG=0.727, 95%CI=0.580-0.911), CC genotype of rs3025040 in VEGFA gene(ORCC/TT=2.019, 95%CI=1.068-3.819). The following genotypes were associated with NG(P<0.05): AG genotype of rs3024997 in VEGFA gene(ORAG/GG=0.628,95%CI=0.478-0.825). The following genotypes were associated with gender disparity in NG(P<0.05): AG genotype of rs3024997 in VEGFA gene(ORAG/GG=0.618,95%CI=0.449-0.851).4. The following alleles were associated with PTC(P<0.05): A allele of rs12427141 in KRAS gene(ORA/G=1.222, 95%CI=1.004-1.487) increased the risk, G allele of rs6566 in MET gene(ORG/A=1.177, 95%CI=1.031-1.344) increased the risk.The following alleles were associated with gender disparity in PTC(P<0.05): T allele of rs712 in KRAS gene(ORT/G=1.254, 95%CI=1.040-1.513) increased the risk, A allele of rs12427141 in KRAS gene(ORA/G=1.272, 95%CI=1.017-1.590) increased the risk, T allele of rs12628 in HRAS gene(ORT/C=1.269, 95%CI=1.042-1.545)increased the risk, G allele of rs1621 in MET gene(ORG/A=1.272,95%CI=1.000-1.618) increased the risk, G allele of rs6566 in MET gene(ORG/A=1.192, 95%CI=1.023-1.388) increased the risk, C allele of rs3025040 in VEGFA gene(ORC/T=1.290, 95%CI=1.058-1.574) increased the risk, T allele of rs25648 in VEGFA gene(ORT/C=1.550, 95%CI=1.116-2.152) increased the risk. The following alleles were associated with NG(P<0.05): T allele of rs12628 in HRAS gene(ORT/C=1.275, 95%CI=1.064-1.640) increased the risk, C allele of rs14804 in NRAS gene(ORC/T=0.655, 95%CI=0.401-0.975) decreased the risk, C allele of rs3025040 in VEGFA gene(ORC/T=1.247, 95%CI=1.026-1.583) increased the risk.The following genotypes were associated with gender disparity in NG(P<0.05): C allele of rs3025040 in VEGFA gene(ORC/T=1.333, 95%CI=1.035-1.716) increased the risk.5. There was a significant difference on rs712-rs12427141, rs1621-rs6566 and rs712-rs12427141-rs7315339 between PTC group and NC group.Conclusion1. MET gene and KRAS gene in MAPK pathway were associated with PTC. GA genotype of rs1621 in MET gene, GG genotype and A → G mutation of rs6566 in MET gene, GT genotype of rs712 in KRAS gene, AA genotype and G→A mutation of rs12427141 in KRAS gene may be risk factors of PTC.2. HRAS gene, NRAS gene and VEGFA gene were associated with NG. C→T mutation of rs12628 in HRAS gene, T→C mutation of rs3025040 in VEGFA gene may be risk factors of NG. T → C mutation of rs14804 in NRAS gene and AG genotype of rs3024997 in VEGFA gene may be protective factors of NG.3. KRAS gene, HRAS gene, MET gene, ALK gene and VEGFA gene were associated with PTC in female. GT genotype and G→T mutation of rs712 in KRAS gene, AA genotype and G→A mutation of rs12427141 in KRAS gene, CC genotype and T→C mutation of rs3025040 in VEGFA gene, CT genotype and C→T mutation of rs25648 in VEGFA gene, C → T mutation of rs12628 in HRAS gene, A → G mutation of rs1621 and A→G mutation of rs6566 in MET gene may be risk factors for female PTC. GC genotype of rs1881421 in ALK gene may be protective factors for female PTC.4. VEGFA gene was associated with NG in female. T→C mutation of rs3025040 in VEGFA gene may be risk factors for female NG. AG genotype of rs3024997 in VEGFA gene and may be protective factors for female NG.5. Haplotype rs712-rs12427141, haplotype rs1621-rs6566 and haplotype rs712-rs12427141-rs7315339 had some association on papillary thyroid carcinoma.6. There was no common gene for PTC and NG in MAPK pathway except rs3025040 in VEGFA gene was the common gene between female PTC and female NG.7. MAPK pathway Gene polymorphism was associated with papillary thyroid carcinoma. |
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