2. Academic Validation
  3. Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation

Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation

  • Nat Genet. 2017 Jul;49(7):1148-1151. doi: 10.1038/ng.3883.
Shawn Yost # 1,  Bas de Wolf # 2,  Sandra Hanks # 1,  Anna Zachariou 1,  Chiara Marcozzi 3 4,  Matthew Clarke 1,  Richarda de Voer 2,  Banafsheh Etemad 2,  Esther Uijttewaal 2,  Emma Ramsay 1,  Harriet Wylie 1,  Anna Elliott 1,  Susan Picton 5,  Audrey Smith 6,  Sarah Smithson 7,  Sheila Seal 1,  Elise Ruark 1,  Gunnar Houge 8,  Jonathan Pines 3 4,  Geert J P L Kops 2 9 10,  Nazneen Rahman 1 11
Affiliations

Affiliations

  • 1 Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK.
  • 2 Hubrecht Institute - KNAW (Royal Netherlands Academy of Arts and Sciences), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
  • 3 The Gurdon Institute and Department of Zoology, University of Cambridge, Cambridge CB2 1QN, UK.
  • 4 Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
  • 5 Children's and Adolescent Oncology and Haematology Unit, Leeds General Infirmary, Leeds, LS1 3EX, UK.
  • 6 Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, UK.
  • 7 Clinical Genetics Service, St Michael's Hospital, Southwell Street, Bristol, BS2 8EG, UK.
  • 8 Center for Medical Genetics, Haukeland University Hospital, N-5021 Bergen, Norway.
  • 9 Cancer Genomics Netherlands, Utrecht, The Netherlands.
  • 10 Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
  • 11 Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK SM2 5PT, UK.
  • # Contributed equally.
PMID: 28553959 DOI: 10.1038/ng.3883
Abstract

Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor. Constitutional mosaic aneuploidies, microcephaly, developmental delay and seizures, which are features of mosaic variegated aneuploidy (MVA) syndrome, were more variably present. Through functional studies, we show that TRIP13-mutant patient cells have no detectable TRIP13 and have substantial impairment of the spindle assembly checkpoint (SAC), leading to a high rate of chromosome missegregation. Accurate segregation, as well as SAC proficiency, is rescued by restoring TRIP13 function. Individuals with biallelic TRIP13 or BUB1B mutations have a high risk of embryonal tumors, and here we show that their cells display severe SAC impairment. MVA due to biallelic CEP57 mutations, or of unknown cause, is not associated with embryonal tumors and cells from these individuals show minimal SAC deficiency. These data provide insights into the complex relationships between aneuploidy and carcinogenesis.

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