Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.
Mol Cancer Res. 2022 Oct 4;20(10):1481-1488. doi: 10.1158/1541-7786.MCR-21-0775.
Chromosomal rearrangements often result in active regulatory regions juxtaposed upstream of an oncogene to generate an expressed gene fusion. Repeated activation of a common downstream partner-with differing upstream regions across a patient cohort-suggests a conserved oncogenic role. Analysis of 9,638 patients across 32 solid tumor types revealed an annotated long noncoding RNA (lncRNA), Breast Cancer Anti-Estrogen Resistance 4 (BCAR4), was the most prevalent, uncharacterized, downstream gene fusion partner occurring in 11 cancers. Its oncogenic role was confirmed using multiple cell lines with endogenous BCAR4 gene fusions. Furthermore, overexpressing clinically prevalent BCAR4 gene fusions in untransformed cell lines was sufficient to induce an oncogenic phenotype. We show that the minimum common region to all gene fusions harbors an open reading frame that is necessary to drive proliferation.
BCAR4 gene fusions represent an underappreciated class of gene fusions that may have biological and clinical implications across solid tumors.
染色体重排常导致活性调控区域与癌基因上游毗邻，从而产生表达的基因融合。在患者队列中，常见下游靶基因与不同的上游区域重复激活，提示其具有保守的致癌作用。对 32 种实体瘤类型的 9638 例患者进行分析，发现注释的长非编码 RNA（lncRNA），即乳腺癌抗雌激素耐药 4（BCAR4），是最常见的、无特征的下游基因融合伙伴，发生于 11 种癌症中。使用具有内源性 BCAR4 基因融合的多种细胞系证实了其致癌作用。此外，在未转化的细胞系中过表达临床上常见的 BCAR4 基因融合足以诱导致癌表型。我们表明，所有基因融合的最小共有区域含有一个开放阅读框，该框是驱动增殖所必需的。
BCAR4 基因融合代表了一类被低估的基因融合，可能在实体瘤中具有生物学和临床意义。
