Department of Pathology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
UCB Pharma, Bath Road, Slough, SL1 3WE, UK.
Nat Commun. 2019 Jul 17;10(1):3134. doi: 10.1038/s41467-019-10966-8.
OPCML, a tumor suppressor gene, is frequently silenced epigenetically in ovarian and other cancers. Here we report, by analysis of databases of tumor sequences, the observation of OPCML somatic missense mutations from various tumor types and the impact of these mutations on OPCML function, by solving the X-ray crystal structure of this glycoprotein to 2.65 Å resolution. OPCML consists of an extended arrangement of three immunoglobulin-like domains and homodimerizes via a network of contacts between membrane-distal domains. We report the generation of a panel of OPCML variants with representative clinical mutations and demonstrate clear phenotypic effects in vitro and in vivo including changes to anchorage-independent growth, interaction with activated cognate receptor tyrosine kinases, cellular migration, invasion in vitro and tumor growth in vivo. Our results suggest that clinically occurring somatic missense mutations in OPCML have the potential to contribute to tumorigenesis in a variety of cancers.
OPCML 是一种肿瘤抑制基因，在卵巢癌和其他癌症中经常因表观遗传沉默。在这里，我们通过分析肿瘤序列数据库报告了从各种肿瘤类型中观察到的 OPCML 体细胞错义突变，以及这些突变对 OPCML 功能的影响，方法是通过解决该糖蛋白的 X 射线晶体结构达到 2.65Å 分辨率。OPCML 由三个免疫球蛋白样结构域的扩展排列组成，并通过膜远端结构域之间的网络相互作用形成同源二聚体。我们报告了一组具有代表性临床突变的 OPCML 变体的产生，并在体外和体内证明了明显的表型效应，包括锚定非依赖性生长、与激活的同源受体酪氨酸激酶相互作用、细胞迁移、体外侵袭和体内肿瘤生长的变化。我们的结果表明，OPCML 中临床出现的体细胞错义突变有可能导致多种癌症的肿瘤发生。
