早发性乳腺癌的遗传易感基因及临床特征

Genetic susceptibility genes and clinical features of early-onset breast cancer

目的探讨中国早发性(发病年龄≤35岁)乳腺癌遗传易感基因的胚系突变率及临床特征。方法收集2015年1月1日至2019年12月31日中国医学科学院北京协和医学院肿瘤医院收治的150例发病年龄≤35岁的乳腺癌患者的临床信息和外周血标本,提取DNA检测乳腺癌易感基因(BRCA)1、BRCA2、毛细血管扩张性共济失调突变(ATM)、BRCA2定位协作基因(PALB2)、肿瘤蛋白53(TP53)和细胞周期检查点激酶2(CHEK2)基因的胚系突变。根据遗传变异的分类标准与指南对突变进行解读,分为致病、可能致病、意义未明、可能良性和良性。根据有无携带致病或可能致病胚系突变,将患者分为突变组(n=18)和非突变组(n=132),采用χ^(2)检验分析组间遗传易感基因胚系突变与临床病理特征的关系。结果150例早发性乳腺癌中检测到18例致病或可能致病胚系突变,总突变率为12.0%。其中,8例(5.3%)BRCA2突变,7例(4.7%)BRCA1突变,1例(0.7%)PALB2突变,2例(1.3%)TP53突变,ATM和CHEK2基因未检测到致病或可能致病突变。突变类型以移码突变(9/18,50.0%)为主,其次是无义突变(7/18,38.9%),错义突变(1/18,5.6%)和剪接受体突变(1/18,5.6%)。18例突变携带者分子分型中,9例Luminal B,6例三阴性乳腺癌(TNBC),2例Luminal A,人表皮生长因子受体-2(HER-2)扩增仅1例。其中,8例BRCA2突变携带者均为Luminal分型,7例BRCA1突变携带者中6例是TNBC分型。突变组和非突变组乳腺癌患者家族史(P=0.343)、雌激素受体(ER)状态(χ^(2)=0.16,P=0.688)、HER-2状态(χ^(2)=2.89,P=0.089)、分子分型(χ^(2)=1.99,P=0.575)、初诊TNM分期(χ^(2)=2.49,P=0.115)差异均无统计学意义。结论早发性乳腺癌具有较高的胚系突变率,建议早发性乳腺癌患者进行遗传咨询和多基因检测。

Objective To explore the germline mutation frequency of genetic susceptibility genes and clinical characteristics in early-onset breast cancer(onset age≤35 years)in China.Methods Clinical information and peripheral blood of 150 patients aged 35 and younger diagnosed with breast cancer in Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College from January 1,2015 to December 31,2019 were collected.Then DNA was extracted to detect germline mutations in breast cancer susceptibility gene(BRCA)1,BRCA2,ataxia telangiectasia mutated(ATM),partner and localizer of BRCA2(PALB2),tumor protein 53(TP53)and cell cycle checkpoint kinase 2(CHEK2)genes.Mutations were interpreted as pathogenic,likely pathogenic,uncertain significance,likely benign and benign according to the classification criteria and guidelines for genetic variation.Patients were divided into mutation group(n=18)and non-mutation group(n=132)according to the presence or absence of pathogenic or probable pathogenic germline mutations,and theχ^(2) test was used to analyze the relationships between genetic susceptibility gene mutations and clinicopathological characteristics.Results Eighteen pathogenic or likely pathogenic germline mutations were detected in 150 patients with early-onset breast cancer,for an overall mutation frequency of 12.0%.Among them,there were 8(5.3%)BRCA2 mutation,7(4.7%)BRCA1 mutation,1(0.7%)PALB2 mutation,and 2(1.3%)TP53 mutation.There were no pathogenic or likely pathogenic variants in ATM and CHEK2 genes.The mutation type was dominated by frameshift mutation(9/18,50.0%),followed by nonsense mutation(7/18,38.9%),missense mutation(1/18,5.6%)and splice acceptor mutation(1/18,5.6%).Among the molecular subtypes of 18 mutation carriers,9 cases were Luminal B,6 cases were triple negative breast cancer(TNBC),2 cases were Luminal A,and only 1 case was human epidermal growth factor receptor-2(HER-2)amplification.Among them,8 BRCA2 mutation carriers were Luminal type,and 6 of 7 BRCA1 mutation carriers were TNBC type.There were no statistical differences in family history of breast cancer(P=0.343),estrogen receptor(ER)status(χ^(2)=0.16,P=0.688),HER-2 status(χ^(2)=2.89,P=0.089),molecular subtype(χ^(2)=1.99,P=0.575),and initial diagnosis TNM stage(χ^(2)=2.49,P=0.115)between the mutation group and the non-mutation group.Conclusion The patients with early-onset breast cancer have high frequency of germline mutations.It is recommended that patients with early-onset breast cancer undergo genetic counseling and multigene testing.