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Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children

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OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djaa133

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  1. US National Institutes of Health [CA21765, CA98543, CA114766, CA98413, CA180886, CA180899, GM92666, GM115279, CA234490, CA197695, GM097119]
  2. American Lebanese Syrian Associated Charities
  3. National Medical Research Council Singapore Research Training Fellowship [003/008-258]
  4. Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning
  5. National Natural Science Foundation of China [81973997]

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A risk locus between BCL11A and PAPOLG was identified in a study on ALL cases, with a subtype-specific effect on TCF3-PBX1 ALL. The risk variant may distally modulate the transcription of the adjacent gene REL through a regulatory DNA element activated uniquely in ALL cells with the TCF3-PBX1 fusion.
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 x 10(-8) for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 x 10(-8) for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis.

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