Genomic and Functional Overlap between Somatic and Germline Chromosomal Rearrangements

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
DOI: 10.1016/j.celrep.2014.11.022 Publication Date: 2014-12-11T13:41:13Z
ABSTRACT
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.
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