van Heesch Sebastiaan, Simonis Marieke, van Roosmalen Markus J, Pillalamarri Vamsee, Brand Harrison, Kuijk Ewart W, de Luca Kim L, Lansu Nico, Braat A Koen, Menelaou Androniki, Hao Wensi, Korving Jeroen, Snijder Simone, van der Veken Lars T, Hochstenbach Ron, Knegt Alida C, Duran Karen, Renkens Ivo, Alekozai Najla, Jager Myrthe, Vergult Sarah, Menten Björn, de Bruijn Ewart, Boymans Sander, Ippel Elly, van Binsbergen Ellen, Talkowski Michael E, Lichtenbelt Klaske, Cuppen Edwin, Kloosterman Wigard P
Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
Cell Rep. 2014 Dec 24;9(6):2001-10. doi: 10.1016/j.celrep.2014.11.022. Epub 2014 Dec 11.
Genomic rearrangements are a common cause of human congenital abnormalities. However, their origin and consequences are poorly understood. We performed molecular analysis of two patients with congenital disease who carried de novo genomic rearrangements. We found that the rearrangements in both patients hit genes that are recurrently rearranged in cancer (ETV1, FOXP1, and microRNA cluster C19MC) and drive formation of fusion genes similar to those described in cancer. Subsequent analysis of a large set of 552 de novo germline genomic rearrangements underlying congenital disorders revealed enrichment for genes rearranged in cancer and overlap with somatic cancer breakpoints. Breakpoints of common (inherited) germline structural variations also overlap with cancer breakpoints but are depleted for cancer genes. We propose that the same genomic positions are prone to genomic rearrangements in germline and soma but that timing and context of breakage determines whether developmental defects or cancer are promoted.
基因组重排是人类先天性异常的常见原因。然而，它们的起源和后果却知之甚少。我们对两名患有先天性疾病且携带新生基因组重排的患者进行了分子分析。我们发现，两名患者的重排均涉及在癌症中经常发生重排的基因（ETV1、FOXP1和微小RNA簇C19MC），并驱动形成了类似于癌症中所描述的融合基因。随后，对552个先天性疾病潜在的新生种系基因组重排进行的大量分析显示，癌症中重排的基因出现富集，且与体细胞癌断点存在重叠。常见（遗传）种系结构变异的断点也与癌断点重叠，但癌症基因数量减少。我们提出，相同的基因组位置在种系和体细胞中都易于发生基因组重排，但断裂的时间和背景决定了是促进发育缺陷还是癌症的发生。
