Genomic and Functional Overlap between Somatic and Germline Chromosomal Rearrangements

• DOI: 10.1016/j.celrep.2014.11.022
• Publication Date: 2014-12-11T13:41:13Z
• Authors: Sebastiaan van He...; Marieke Simonis; Markus J. van Roo...; Vamsee Pillalamarri; Harrison Brand; Ewart W. Kuijk; Kim L. de Luca; Nico Lansu; A. Koen Braat; Androniki Menelaou; Wensi Hao; Jeroen Korving; Simone Snijder; Lars T. van der V...; Ron Hochstenbach; Alida C. Knegt; Karen Duran; Ivo Renkens; Najla Alekozai; Myrthe Jager; Sarah Vergult; Björn Menten; Ewart de Bruijn; Sander Boymans; Elly Ippel; Ellen van Binsbergen; Michael E. Talkowski; Klaske Lichtenbelt; Edwin Cuppen; Wigard P. Klooste...
• Keywords: 0301 basic medicine; QH301-705.5; AUTISM SPECTRUM DISORDERS; DE-NOVO; Congenital Abnormalities; Chromosome Breakpoints; 03 medical and health sciences; Animals; Chromosomes, Human; Humans; Biology (General); Germ-Line Mutation; Zebrafish; COPY NUMBER VARIATION; REPAIR; Chromosome Aberrations; Gene Rearrangement; ETV1; IDENTIFICATION; ABNORMALITIES; Genome, Human; Biology and Life Sciences; Forkhead Transcription Factors; GENE FUSIONS; Radboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences; PROSTATE-CANCER; 3. Good health; STRUCTURAL VARIATION; DNA-Binding Proteins; Repressor Proteins; MicroRNAs; HEK293 Cells; Transcription Factors

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.