University of Oulu

Tekla Järviaho, Benedicte Bang, Vasilios Zachariadis, Fulya Taylan, Jukka Moilanen, Merja Möttönen, C. I. Edvard Smith, Arja Harila-Saari, Riitta Niinimäki, Ann Nordgren; Predisposition to childhood acute lymphoblastic leukemia caused by a constitutional translocation disrupting ETV6. Blood Adv 2019; 3 (18): 2722–2731. doi:

Predisposition to childhood acute lymphoblastic leukemia caused by a constitutional translocation disrupting ETV6

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Author: Järviaho, Tekla1,2,3; Bang, Benedicte4; Zachariadis, Vasilios4,5;
Organizations: 1PEDEGO Research Unit, University of Oulu, Oulu, Finland
2Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
3Biocenter Oulu, University of Oulu, Oulu, Finland
4Department of Molecular Medicine and Surgery, Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
5Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
6Department of Clinical Genetics, Oulu University Hospital,Oulu, Finland
7Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
8Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
9Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.3 MB)
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Language: English
Published: American Society of Hematology, 2019
Publish Date: 2020-02-26


Pathogenic germline variants in ETV6 have been associated with familial predisposition to thrombocytopenia and hematological malignancies, predominantly childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In addition, overrepresentation of a high hyperdiploid subtype and older age at diagnosis have been reported among sporadic BCP-ALL cases with germline variants in ETV6. We studied a family with 2 second-degree relatives who developed childhood high hyperdiploid BCP-ALL at ages 8 and 12 years, respectively. A constitutional balanced reciprocal translocation t(12;14)(p13.2;q23.1) was discovered in both patients by routine karyotyping at diagnosis and, subsequently, in 7 healthy family members who had not experienced hematological malignancies. No carriers had thrombocytopenia. Whole-genome sequencing confirmed the translocation, resulting in 2 actively transcribed but nonfunctional fusion genes, causing heterozygous loss and consequently monoallelic expression of ETV6. Whole-genome sequencing analysis of the affected female subjects’ leukemia excluded additional somatic aberrations in ETV6 and RTN1 as well as shared somatic variants in other genes. Expression studies, performed to confirm decreased expression of ETV6, were not conclusive. We suggest that germline aberrations resulting in monoallelic expression of ETV6 contribute to leukemia susceptibility, whereas more severe functional deficiency of ETV6 is required for developing THC5. To our knowledge, this report is the first of a constitutional translocation disrupting ETV6 causing predisposition to childhood ALL.

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Series: Blood advances
ISSN: 2473-9529
ISSN-E: 2473-9537
ISSN-L: 2473-9529
Volume: 3
Issue: 18
Pages: 2722 - 2731
DOI: 10.1182/bloodadvances.2018028795
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
3123 Gynaecology and paediatrics
Funding: This work was supported by grants from the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, the Cancer Research Funds of Radiumhemmet, the Swedish Research Council, Berth von Kantzow’s foundation, the Mary Béve Foundation for Pediatric Cancer Research, Karolinska Institutet, the Alma and K. A. Snellman Foundation, Maud Kuistila Memorial Foundation, the Finnish Foundation for Pediatric Research, and Väre Foundation for Pediatric Cancer Research.
Copyright information: © 2019 by The American Society of Hematology.