Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia


Autoři: Gayle P. Pouliot aff001;  James Degar aff001;  Laura Hinze aff001;  Bose Kochupurakkal aff003;  Chau D. Vo aff001;  Melissa A. Burns aff001;  Lisa Moreau aff001;  Chirag Ganesa aff003;  Justine Roderick aff004;  Sofie Peirs aff005;  Bjorn Menten aff005;  Mignon L. Loh aff006;  Stephen P. Hunger aff007;  Lewis B. Silverman aff001;  Marian H. Harris aff008;  Kristen E. Stevenson aff009;  David M. Weinstock aff010;  Andrew P. Weng aff011;  Pieter Van Vlierberghe aff005;  Alan D. D’Andrea aff001;  Alejandro Gutierrez aff001
Působiště autorů: Division of Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts, United States of America aff001;  Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America aff002;  Center for DNA Damage and Repair and Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America aff003;  Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America aff004;  Department of Biomolecular Medicine, Ghent University, Ghent, Belgium aff005;  Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America aff006;  Division of Oncology and the Center for Childhood Cancer Research, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America aff007;  Department of Pathology, Boston Children’s Hospital, Boston, Massachusetts, United States of America aff008;  Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America aff009;  Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America aff010;  Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada aff011
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0221288

Souhrn

BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination.

Klíčová slova:

Gene sequencing – Genetic causes of cancer – Mutation – Point mutation – Polymerase chain reaction – Haploinsufficiency – Dideoxy DNA sequencing


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