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

• Published in: Blood advances Vol. 3; no. 18; pp. 2722 - 2731
• Main Authors: Järviaho, Tekla, Bang, Benedicte, Zachariadis, Vasilios, Taylan, Fulya, Moilanen, Jukka, Möttönen, Merja, Smith, C.I. Edvard, Harila-Saari, Arja, Niinimäki, Riitta, Nordgren, Ann
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.09.2019; American Society of Hematology; Elsevier
• Subjects: Child; ETS Translocation Variant 6 Protein; Female; Genetic Predisposition to Disease - genetics; Humans; Lymphoid Neoplasia; Male; Medicin och hälsovetenskap; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Proto-Oncogene Proteins c-ets - genetics; Repressor Proteins - genetics; Translocation, Genetic
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2018028795

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. •We report the first known family with a constitutional translocation disrupting ETV6 predisposing to ALL.•Germline monoallelic expression of ETV6 contributes to leukemia predisposition without thrombocytopenia. [Display omitted]