子宫颈鳞状细胞癌基因胚系突变特点及与临床特征的关系  

The Relationship between Germline Mutant Characteristics and Clinical Features of Cervical Squamous Cell Carcinoma Genes

作　　者：姜德文 李彬 何冬玲 傅晓丽 周箫 吕庆 刘艳洁[1,2] JIANG Dewen;LI Bin;HE Dongling(Department of Pathology,Guizhou Medical University,Guiyang Guizhou 550004,China;Department of Pathology,Affiliated Hospital of Guizhou Medical University,Guiyang Guizhou 550004,China;Department of Occupational Diseases,Third People′s Hospital of Guizhou Province,Guiyang Guizhou 550004,China)

机构地区：[1]贵州医科大学病理学教研室,贵州贵阳550004 [2]贵州医科大学附属医院病理科,贵州贵阳550004 [3]贵州省第三人民医院职业病科,贵州贵阳550004

出　　处：《实用妇产科杂志》2023年第6期454-459,共6页Journal of Practical Obstetrics and Gynecology

基　　金：贵州省科技厅科技支撑计划资助[编号:(2019)2791];贵阳市科技计划资助[编号:(2019)9-1-16]。

摘　　要：目的:探讨子宫颈鳞状细胞癌(CSCC)基因胚系突变特点及与临床特征的关系。方法:选取67例CSCC患者的癌组织和癌旁组织,提取组织样本的基因组DNA、构建基因组文库和杂交捕获胚系突变基因的外显子序列进行有效PCR扩增和富集;采用二代测序(NGS)技术检测基因胚系突变情况并对其突变位点进行筛选、分类和分析。结果:57例发生胚系突变的CSCC患者组织样本共检出46种胚系突变基因及其相应的125个突变位点。46种胚系突变基因在CSCC患者中排名前10位的为FANCA、MSH2、BRCA2、BRCA1、BRIP1、TSC1、PTCH1、MSH6、CHEK2和CDKN2A,其中FANCA、BRCA2、MSH2、BRCA1及BRIP1等30种基因突变出现在2例及以上的患者中;这些突变分别发生在常染色体和X染色体上,其突变类型分别为3个移码缺失突变、112个非同义突变、4个同义突变、2个非移码缺失突变、1个终止突变和3个可变剪切位点突变。在125个突变位点中有24个(19.20%)位点发生致病性突变和101个(80.80%)位点发生非致病性突变。24个致病突变位点发生在19例CSCC患者对应的11种基因(FANCA、BRCA1、BRCA2、MSH2、PALB2、BRIP1、ATR、CHEK2、FLCN、MRE11A和NF2)中,其中新发现5个突变位点BRCA1(c.2350del:p.S784Rfs*8)、MRE11A(c.1532del:p.N511Ifs*13)、NF2(c.1724del:p.N575Ifs*24)、ATR(c.1222A>G:p.I408V)和BRIP1(c.3391T>C:p.Y1131H)在CLINVAR和HGMD数据库中未收录。统计分析结果显示,基因胚系突变在绝经状态和病理分化程度中差异有统计学意义(P<0.05),胚系突变位点的变异类型也仅在非同义突变中差异有统计学意义(P<0.05)。结论:11种基因的致病性突变是潜在地促进CSCC发生、发展的重要因素,其致病性突变位点可能是CSCC发生更加密切相关的致病位点。新发现的5个突变位点可能参与CSCC发生和发展的致病机制,有望成为CSCC未来需要关注的突变位点。Objective:To investigate the relationship between germline mutant characteristics and clinical features of cervical squamous cell carcinoma(CSCC)genes.Methods:The genomic DNA of 67 CSCC patients were extracted,genomic libraries were constructed and the exon sequences of germline mutations were captured by hybridization for effective PCR amplification and enrichment.The germline mutations were detected by next-generation sequencing(NGS)technology and the mutant sites were screened,classified and analyzed.Results:A total of 46 germline mutated genes and their corresponding 125 mutant sites were detected in tissue samples from 57 CSCC patients.The top ten of 46 germline mutat genes in CSCC patients were FANCA,MSH 2,BRCA 2,BRCA1,BRIP 1,TSC 1,PTCH 1,MSH 6,CHEK 2 and CDKN 2A.30 of these mutated genes included in FANCA,BRCA 2,MSH 2,BRCA1 and BRIP 1 were found in two or more patients.These mutations occurred on the autosomes and X chromosome,with three frameshift deletions,112 nonsynonymous SNVs,4 synonymous SNVs,2 non-frameshift deletions,1 stopgain mutation and 3 variable splice site mutations.We found pathogenic mutations occurred at 24(19.20%)of the 125 mutant sites and non-pathogenic mutations at 101(80.80%)of the sites.The 24 pathogenic mutations occurred in 11 genes(FANCA,BRCA1,BRCA2,MSH2,PALB2,BRIP1,ATR,CHEK2,FLCN,MRE11A and NF2)corresponding to 19 cases of CSCC.We further found that 5 mutant sites which included BRCA 1(c.2350del:p.S784Rfs*8),MRE11A(c.1532del:p.N511Ifs*13),NF2(c.1724del:p.N575Ifs*24),ATR(c.1222A>G:p.I408V)and BRIP1(c.3391T>C:p.Y1131H)were not collected in the CLINVAR and HGMD databases.The statistical analysis showed that the differences in the state of menopause and the degree of differentiation of gene germline mutations were statistically significant(P<0.05),the type of variations in germline mutant sites was also statistically significant(P<0.05)only in nonsynonymous SNVs.Conclusions:Pathogenic mutations in 11 genes are potentially important factors contributing to the development of CSCC,and

关 键 词：子宫颈鳞状细胞癌 基因 胚系突变 临床特征 

分 类 号：R737.33[医药卫生—肿瘤]