Imielinski Marcin, Guo Guangwu, Meyerson Matthew
Department of Pathology and Laboratory Medicine, Englander Institute for Precision Medicine, Institute for Computational Biomedicine, and Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; New York Genome Center, New York, NY 10013, USA.
Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Cell. 2017 Jan 26;168(3):460-472.e14. doi: 10.1016/j.cell.2016.12.025. Epub 2017 Jan 12.
Certain cell types function as factories, secreting large quantities of one or more proteins that are central to the physiology of the respective organ. Examples include surfactant proteins in lung alveoli, albumin in liver parenchyma, and lipase in the stomach lining. Whole-genome sequencing analysis of lung adenocarcinomas revealed noncoding somatic mutational hotspots near VMP1/MIR21 and indel hotspots in surfactant protein genes (SFTPA1, SFTPB, and SFTPC). Extrapolation to other solid cancers demonstrated highly recurrent and tumor-type-specific indel hotspots targeting the noncoding regions of highly expressed genes defining certain secretory cellular lineages: albumin (ALB) in liver carcinoma, gastric lipase (LIPF) in stomach carcinoma, and thyroglobulin (TG) in thyroid carcinoma. The sequence contexts of indels targeting lineage-defining genes were significantly enriched in the AATAATD DNA motif and specific chromatin contexts, including H3K27ac and H3K36me3. Our findings illuminate a prevalent and hitherto unrecognized mutational process linking cellular lineage and cancer.
某些细胞类型起着工厂的作用，分泌大量对相应器官生理功能至关重要的一种或多种蛋白质。例如肺泡中的表面活性物质蛋白、肝实质中的白蛋白以及胃黏膜中的脂肪酶。肺腺癌的全基因组测序分析揭示了VMP1/MIR21附近的非编码体细胞突变热点以及表面活性物质蛋白基因（SFTPA1、SFTPB和SFTPC）中的插入缺失热点。将其外推至其他实体癌，发现了高度复发且肿瘤类型特异性的插入缺失热点，这些热点靶向定义某些分泌细胞谱系的高表达基因的非编码区域：肝癌中的白蛋白（ALB）、胃癌中的胃脂肪酶（LIPF）以及甲状腺癌中的甲状腺球蛋白（TG）。靶向谱系定义基因的插入缺失的序列背景在AATAATD DNA基序和特定染色质背景（包括H3K27ac和H3K36me3）中显著富集。我们的研究结果揭示了一种将细胞谱系与癌症联系起来的普遍且迄今未被认识的突变过程。
