Dopeso Higinio, Gazzo Andrea M, Derakhshan Fatemeh, Brown David N, Selenica Pier, Jalali Sahar, Da Cruz Paula Arnaud, Marra Antonio, da Silva Edaise M, Basili Thais, Gusain Laxmi, Colon-Cartagena Lorraine, Bhaloo Shirin Issa, Green Hunter, Vanderbilt Chad, Oesterreich Steffi, Grabenstetter Anne, Kuba M Gabriela, Ross Dara, Giri Dilip, Wen Hannah Y, Zhang Hong, Brogi Edi, Weigelt Britta, Pareja Fresia, Reis-Filho Jorge S
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
NPJ Precis Oncol. 2024 Feb 12;8(1):33. doi: 10.1038/s41698-024-00508-x.
CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC.
CDH1（E-钙黏蛋白）双等位基因失活是乳腺浸润性小叶癌（ILC）的标志性改变，导致其出现分散的表型。然而，一部分ILC缺乏CDH1基因/表观遗传失活，其遗传基础尚不清楚。通过对364例原发性ILC的临床靶向测序数据进行重新分析，我们鉴定出25例缺乏CDH1双等位基因遗传改变的ILC。在这些病例中，CDH1启动子甲基化很常见（63%）。靶向测序重新分析发现3例ILC携带AXIN2有害融合（n = 2）或功能丧失突变（n = 1）。对3例缺乏CDH1双等位基因遗传/表观遗传失活的病例进行全基因组测序，证实了AXIN2突变，且未发现其他细胞间黏附基因改变，但发现了一种新的CTNND1（p120）有害融合。在MCF7细胞中敲除AXIN2会导致小叶样特征，包括细胞迁移增加和对失巢凋亡的抗性增强。综上所述，缺乏CDH1基因/表观遗传改变的ILC是由其他细胞黏附基因（CTNND1或AXIN2）的失活改变驱动的，这支持了ILC中的趋同表型。
