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Blood Adv. 2019 Apr 9;3(7):1039-1046. doi: 10.1182/bloodadvances.2018030635.

Germline deletion of ETV6 in familial acute lymphoblastic leukemia.

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Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN.
Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
Childrens Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Department of Pathology, St. Jude Children's Research Hospital, Memphis TN.
Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Sloan Kettering Institute, New York, NY.
Hereditary Cancer Centre, Prince of Wales Hospital, Sydney, NSW, Australia.
Prince of Wales Clinical School University of NSW Australia, Sydney, NSW, Australia.
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; and.
South Eastern Area Laboratory Service, Prince of Wales Hospital, Randwick, NSW, Australia.


Recent studies have identified germline mutations in TP53, PAX5, ETV6, and IKZF1 in kindreds with familial acute lymphoblastic leukemia (ALL), but the genetic basis of ALL in many kindreds is unknown despite mutational analysis of the exome. Here, we report a germline deletion of ETV6 identified by linkage and structural variant analysis of whole-genome sequencing data segregating in a kindred with thrombocytopenia, B-progenitor acute lymphoblastic leukemia, and diffuse large B-cell lymphoma. The 75-nt deletion removed the ETV6 exon 7 splice acceptor, resulting in exon skipping and protein truncation. The ETV6 deletion was also identified by optimal structural variant analysis of exome sequencing data. These findings identify a new mechanism of germline predisposition in ALL and implicate ETV6 germline variation in predisposition to lymphoma. Importantly, these data highlight the importance of germline structural variant analysis in the search for germline variants predisposing to familial leukemia.

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