在所谓的遗传性弥漫性胃癌(HDGC)综合征中,致病性或可能致病性(P/LP)种系CDH1变异与弥漫性胃癌和小叶乳腺癌(LBC)的风险相关。然而,在某些情况下,在没有弥漫性胃癌表现的情况下,LBC可以是该综合征的第一表现。
■为了评估具有遗传性LBC(HLBC)表型的女性中种系CDH1变异的频率,种系CDH1变异携带者肿瘤样本中的体细胞CDH1基因失活,以及基因图谱与临床病理数据和生存率的关联。
■这个单中心,纵向,前瞻性队列研究于1997年1月1日至2021年12月31日进行,随访至2023年1月31日。包括在欧洲肿瘤研究所看到的LBC妇女。进行种系CDH1、BRCA1和BRCA2基因的测试。评估种系CDH1携带者的体细胞谱。
■准确估计HLBC患者种系CDH1变异的患病率以及体细胞序列改变与HLBC综合征的关联.Kaplan-Meier方法和多变量Cox比例风险回归模型用于总体和无病生存分析。
■5429例原发性LBC,家族性LBC表型占1867例(34.4%)。共有394名女性LBC接受了检测,其中鉴定出15个无关家族中的15个种系CDH1变异体。在这些变体中,6(40.0%)为P/LP,总频率为1.5%(394人中的6人)。在P/LPCDH1LBC的6名先证者中,5例(83.3%)有阳性的BC家族史,只有1例(16.7%)有散发性少年早发性LBC。在CDH1携带者中没有鉴定到种系BRCA1和BRCA2变体。在P/LP种系携带者中的6个探索的匹配肿瘤样品中的4个(66.7%)中鉴定了失活CDH1机制(第二次命中)。与携带未知意义或可能良性的CDH1变异的组相比,P/LPCDH1变异的LBC携带者在诊断时的年龄显着降低(42.5[IQR,38.3-43.0]vs51.0[IQR,45.0-53.0]年;P=0.03)。
■在这项队列研究中,P/LP种系CDH1变异体在不符合HDGC筛选的经典临床标准的个体中被鉴定,提示对这些变异的鉴定可能为检测诊断年龄较早和/或有BC家族史的LBC女性提供新的方法.
UNASSIGNED: Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation.
UNASSIGNED: To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers\' tumor samples, and the association of genetic profiles with clinical-pathological data and survival.
UNASSIGNED: This single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers.
UNASSIGNED: Accurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis.
UNASSIGNED: Of 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03).
UNASSIGNED: In this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.