Cell Reports (Dec 2014)
Genomic and Functional Overlap between Somatic and Germline Chromosomal Rearrangements
- Sebastiaan van Heesch,
- Marieke Simonis,
- Markus J. van Roosmalen,
- 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 Veken,
- 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. Kloosterman
Affiliations
- Sebastiaan van Heesch
- Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
- Marieke Simonis
- Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
- Markus J. van Roosmalen
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- Vamsee Pillalamarri
- Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
- Harrison Brand
- Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
- Ewart W. Kuijk
- Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
- Kim L. de Luca
- Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
- Nico Lansu
- Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
- A. Koen Braat
- Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
- Androniki Menelaou
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- Wensi Hao
- Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
- Jeroen Korving
- Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
- Simone Snijder
- Department of Clinical Genetics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Lars T. van der Veken
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- Ron Hochstenbach
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- Alida C. Knegt
- Department of Clinical Genetics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Karen Duran
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- Ivo Renkens
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- Najla Alekozai
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- Myrthe Jager
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- Sarah Vergult
- Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
- Björn Menten
- Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
- Ewart de Bruijn
- Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
- Sander Boymans
- Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
- Elly Ippel
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- Ellen van Binsbergen
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- Michael E. Talkowski
- Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
- Klaske Lichtenbelt
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- Edwin Cuppen
- Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
- Wigard P. Kloosterman
- Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
- DOI
- https://doi.org/10.1016/j.celrep.2014.11.022
- Journal volume & issue
-
Vol. 9,
no. 6
pp. 2001 – 2010
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.
