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Blood Adv. 2019 Sep 24;3(18):2722-2731. doi: 10.1182/bloodadvances.2018028795.

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

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PEDEGO Research Unit, University of Oulu, Oulu, Finland.
Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland.
Biocenter Oulu, University of Oulu, Oulu, Finland.
Department of Molecular Medicine and Surgery, Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Department of Clinical Genetics and.
Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and.
Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.


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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